Topical regional neuro-affective therapy

ABSTRACT

A method of treating a disease state or condition in humans via topical brainstem afferent stimulation therapy via the administration of a drug to the back of the neck of a human patient at the hairline in close proximity to and under or on the area of skin above the brain stem to provide regional neuro-affective therapy is disclosed.

FIELD OF THE INVENTION

The invention relates to topical regional neuro-affective therapy (“TRNATHERAPY”) for the treatment of neuronal hyperexcitability andneurochemical dysfunction syndromes. This is accomplished viaadministration of effective amounts of these agents at the back of theneck at the hairline (“BONATH”).

BACKGROUND OF THE INVENTION

The approximate 2½ pound human brain is comprised of the most complexmaterial known to man. The neuron, the primary functional cell of thenervous system, operates on the basis of electrical impulses that resultin the release of neurochemical substances (neurotransmitters) atspecific receptors: dopamine, serotonin, acetylcholine, norepinephrine,gamma-amino butyric acid (GABA), and many others. There are estimated tobe 80-100 billion (10 times the world population) neurons in the averagehuman brain. These neurons, in turn, make 200-300 billion codedconnections with other neurons to accomplish the complex tasks of thehuman body.

The brainstem serves as the vital pathway for relay and processing ofneural impulses flowing continuously between the brain and the rest ofthe body. It is about the size of the thumb and contains the most denseand complicated wiring systems in the human body. In addition to theaxons and dendrites (wires) that carry nerve impulses, the brainstemalso contains critical nuclei that function as electrical generators andrelays. Some of the nuclei are related to cranial nerve function whileothers serve as generators and impulse centers for pain perception, theautonomic system “fight or flight” response, wakefulness and alertness,as well as cardio-respiratory and related autonomic functions.

In the prior art, there have been previous attempts to provide for amore efficacious and safe treatment using serotonin agonists specificfor the 5-HT1 receptor subtype.

For Example, U.S. Pat. No. 5,863,935 to Robertson et al. describescertain compounds having “5-HT1-like” receptor agonist properties andtheir administration in a number of ways, including topical orintranasal application.

Additionally, U.S. Pat. No. 5,805,571 to List, describes a transdermaltherapeutic system for the systemic administration of active substanceswherein at least one of the active substances listed is a serotoninagonist of the group comprising indole derivatives. Typically,transdermal systems are not used in acute situations because they do notprovide an immediate effect, but rather provide prophylaxis or prolongedeffect through their sustained delivery process. Transdermal systemssuch as that described in the '571 patent to List require a period oftime for the drug to pass through a barrier layer and onto/into the skin(ionophoresis through concentrations gradients) which may take e.g., asubstantial period of time until the dose of drug that is absorbed issufficient to alleviate the pain associated with the headache. Thesepreviously described transdermal systems require the operation of aconcentration gradient for the absorption of topically applied drug toenter the bloodstream through the small blood vessels in the skin andsoft tissues. After entry into the systemic circulation in sufficientquantity to establish a therapeutic level, drug is eventually deliveredby the cerebral blood flow to the target sites. Accordingly, thisprocess involves relative considerable time, not amenable for the acuterelief of symptoms. Furthermore, it is influenced by such factors ascardiac output and cerebrovascular disease that influence blood flow andtissue absorption.

The inventor has previously described the delivery of anti-migrainedrugs (e.g., triptans and ergot alkaloids) and muscle relaxants (e.g.,tizanidine) through topical regional neuro-affective (TRNA) therapy bytopical application (e.g., as a cream/gel or a sustained release patch)applied at the back of the neck at the hairline (BONATH). The author hasdemonstrated the efficacy of this route of delivery for the treatment ofmigraine, another brainstem disorder, using sumatriptan and tizanidinecompounded in an appropriate dermal penetration enhancing medium.

The inventor's previous U.S. Patent Publication No. 20030013753 (filedJun. 5, 2002) and U.S. Patent Publication No. 20080090894, both of whichare hereby incorporated by reference, disclose a unit dose of a topicalformulation for treating a migraine or cluster headache comprising: aserotonin agonist incorporated into a pharmaceutically acceptablevehicle for topical administration onto the skin of a human patient.Preferably, the unit dose providing the serotonin agonist is in a formthat is immediately absorbable when said unit dose is applied onto humanskin. Preferably, the serotonin agonist comprises from about 0.5 toabout 200 mg of sumatriptan, by weight based on the succinate salt, or atherapeutic equivalent dose of another topically absorbablepharmaceutically acceptable serotonin agonist. Preferably, the unit doseprovides relief from a migraine or cluster headache within about 2 hoursafter topical administration to a human patient.

The inventor's previous U.S. Patent Publication No. 20070065463 (filedJun. 21, 2004) discloses a topical formulation for treating migraines orcluster headaches, muscle sprains, muscle spasms, spasticity, tensionheadaches, tension related migraines and related conditions associatedwith muscle tension and pain comprising: a therapeutically effectiveamount of an active agent(s) incorporated into a pharmaceuticallyacceptable excipient for topical administration onto the skin of a humanpatient, the active agent(s) being selected from the group consistingof: i) an ergot alkaloid; ii) a skeletal muscle relaxant; or iii) acombination of an ergot alkaloid and a skeletal muscle relaxant; theactive agent(s) being present in an effective concentration such that aunit dose of the topical formulation provides a therapeutic effectwithin about 2 hours after topical administration to the human patient.In certain preferred embodiments, the topical formulation comprises askeletal muscle relaxant such as tizanidine. In certain preferredembodiments, the unit dose comprises from about 0.4 mg to 8 mg,preferably from about 0.2 mg to about 4 mg of tizanidine hydrochloride.

In instances where humans suffer from conditions involving neuronalhyperexcitability and/or a neurochemical dysfunction syndrome(s),adequate treatment is not generally available. Such conditions includeheadache including migraine, cluster, tension-type headache and therelated menstrual conditions of menstrual migraine. In fact, other suchconditions include, but are not limited to, pain, anxiety reactions,panic attacks, seizures of both epileptic and non-epileptic(psychogenic) varieties; and acute head and face pain syndromes such astrigeminal neuralgia, atypical facial pain, occipital neuralgia, TMJrelated pain, hot flashes, menstrual associated dysphoria, MultipleSclerosis, and Parkinson's Disease and similar or related syndromes.

For example, Parkinson's disease is a common, debilitating, neurologicalcondition of unknown cause. There is no known cure and treatment isdirected at reducing symptoms. It is considered the result of aprogressive degenerative process within the central nervous system(CNS). A significant reduction in brain levels of the neuro-chemicaldopamine is the hallmark characteristic of the disease process. Otherbrain chemicals are also affected. Pathological studies indicate deathand loss of dopamine producing cells within the substantia nigra of thebrainstem. Loss of cells in the caudate and putamen (the striatum) whichrely on dopamine connections from substantia nigra, the ascendingnigra-striatal dopaminergic pathway, also occurs. The resultant cardinalclinical signs of Parkinson's disease are: tremor, postural instability,bradykinesia/rigidity. Depression, autonomic dysfunction, and memorydisturbance/cognitive problems are also common. Parkinson's disease isthe third most common out-patient neurological diagnosis after headachesand seizures.

The mainstay treatment of Parkinson's disease is aimed at normalizingthe reduced central dopamine levels. This is accomplished by eitherproviding exogenous levodopa orally for eventual conversion intodopamine in the brain or the use of dopamine agonists to augment theendogenous dopamine. COMT inhibitors are also used in the therapeuticregimen to reduce the breakdown of dopamine, allowing for higher andmore persistent levels at the receptors. The problem with thesetraditional therapies is that they are unable to provide the stabledopamine levels at the receptors which occur in the natural state. Thefluctuations in dopamine levels result in fluctuations in clinicalfunction: so called “on and off” states. They also affect dopaminereceptor sensitivity in the long term such that “motor complications”and dyskinesias may occur after several years of therapy. This isparticularly true with exogenous dopamine therapy and in patientsdiagnosed in their younger years.

Patients with end-of-dose wearing off phenomena, the most significant ofwhich is “freezing”, where one is essentially paralyzed and unable tomove, are significantly affected in their activities from the suddenepisodic dopamine deficiency at the receptor level.

Apomorphine hydrochloride (Apokyn by Vernalis, which was recentlyacquired by Ipsen Pharmaceuticals) is given as subcutaneous injectionsto counter such “off periods”. It has also been administered viaintra-peritoneal infusion. The drug is reported to take effect within10-15 minutes and last for up to 1% h hours. This allows a patient toengage in pre-planned activities that would otherwise not have beenpursued—going out to dinner, etc. The resultant sense of control overone's disease and associated reduced anxiety for such affected patientsis immeasurable. Apokyn is marketed for use in the treatment of “acute,intermittent treatment of hypomobility, off episodes (end-of-dosewearing off and unpredicatable on/off episodes) associated with advancedParkinson's disease”.

Unfortunately, as an injection, Apokyn has not been a preferred form oftreatment despite its efficacy. It is also associated with a relativehigh cost (approximately $100 for a 3 ml cartridge) not affordable forroutine use by most patients. It involves a titration phase fortolerability and efficacy determination (2 mg or 0.2 ml to 6 mg or 0.6ml) with a nurse at a doctor's office, further contributing to cost andtime. Finally, Apokyn is associated with significant nausea and vomitingto the extent patients are required to take an anti-emetic(trimethobenzamide/Tigan 200-300 mg 3×/day) for 3 days prior to thefirst injection and encouraged to continue the regimen for an additional6 weeks. Despite using Tigan, a significant number of patients stillexperience nausea and vomiting—31% and 11% respectively in reportedclinical trials. Other anti-emetics with anti-dopaminergic actions arecontraindicated as they may worsen the symptoms of Parkinson's. Further,the requirement of medications to counter side-effects contributes toadditional drug-drug interactions. Parkinson's patients are generallyalready on a significant degree of “poly-pharmacy”.

The significant nausea and vomiting associated with apomorphine in oraland injectable forms is likely the result of its direct effect on the“chemoreceptor zone” of the area postrema in the floor of the IVthventricle adjacent to the brainstem. Other commonly reported adverseevents in clinical trials also indicate stimulation of other brainstemstructures, including the autonomic nervous system, by the apomorphinein the cerebral blood: dizziness, yawning, somnolence, rhinorrhea,sweating, flushing, pallor, hallucinations, edema, and chest pain.

Thus, in spite of its effectiveness and potential to improve the livesof persons affected by Parkinson's disease, for the above noted reasons,the use of injectable apomorphine has been limited. Oral forms have notbeen pursued as they are even less well tolerated as the doserequirements are high. Intra-peritoneal and intravenous injections areimpractical.

Apomorphine hydrochloride is a non-ergoline dopamine agonist that islipophilic and soluble in water at 80 degrees Celsius. In vitro testsshow it has a high affinity for the D4 dopamine receptor and moderatefor the D2, D3, and D5 receptors. It also has moderate affinity for somealpha-adrenergic receptors. It has a low affinity for the dopamine D1and serotonin receptors. Although the precise mechanism of action ofapomorphine is unknown, it is believed to work through the stimulationof post-synaptic dopamine D2 receptors in the striatum, the caudate andputamen.

The significant nausea and vomiting associated with apomorphine in oraland injectable forms is likely the result of its direct effect on the“chemoreceptor zone” of the area postrema in the floor of the IVthventricle adjacent to the brainstem. Other commonly reported adverseevents in clinical trials also indicate stimulation of other brainstemstructures, including the autonomic nervous system, by the apomorphinein the cerebral blood: dizziness, yawning, somnolence, rhinorrhea,sweating, flushing, pallor, hallucinations, edema, and chest pain.

For the above reasons, despite its efficacy and potential to improve thelives of persons affected by Parkinson's disease, the use of injectableapomorphine has been limited. Oral forms have not been pursued as theyare even less well tolerated as dose requirements are high.Intra-peritoneal and intravenous injections are impractical but havebeen pursued. Intra-peritoneal apomorphine via continuous infusion pump(such as for insulin), is used in Europe.

SUMMARY OF THE INVENTION

It is an object of the present invention to provide a method oftreatment in humans with topical brainstem deafferentation therapy viathe regional administration of a compound useful for the treatment ofsuch diseases or conditions that may be treated via such therapy.

It is an object of the present invention to provide a method for thetreatment of neuronal hyperexcitability and neurochemical dysfunctionsyndromes including but not limited to pain, anxiety reactions, panicattacks, seizures of both epileptic and non-epileptic (psychogenic)varieties; and acute head and face pain syndromes such as trigeminalneuralgia, atypical facial pain, occipital neuralgia, TMJ related pain,hot flashes, menstrual associated dysphoria, Multiple Sclerosis, andParkinson's Disease and similar or related syndromes.

It is an object of the invention to provide a topical formulation of adopamine agonist(s) useful in the treatment of Parkinson's diseaseand/or related syndromes/diseases.

It is a further object of the invention to provide a method of treatmentof Parkinson's disease and related syndromes/diseases via the topicaladministration of one or more dopamine agonists.

It is a further object of the invention to provide a topical formulationof a dopamine agonist(s) useful in the treatment of Parkinson's diseaseand/or related syndromes/diseases.

It is a further object of the invention to provide a method of treatmentof impotence with erectile dysfunction in men via the topicaladministration of one or more dopamine agonists.

It is a further object of the present invention to provide a method forthe treatment of neuronal hyperexcitability and neurochemicaldysfunction syndromes in humans suffering from Parkinson's diseaseand/or related syndromes/diseases via topical brainstem afferentstimulation therapy via the regional administration of a compound usefulfor the treatment of such diseases or conditions that may be treated viasuch therapy.

It is a further object of the present invention to provide a method oftreatment of impotence/erectile dysfunction in men and/or relatedsyndromes/diseases via topical brainstem afferent stimulation therapyvia the regional administration of a compound useful for the treatmentof such diseases or conditions that may be treated via such therapy.

The above objects and others are attained by virtue of the presentinvention, which is directed in part to a method of treating a diseasestate or condition in humans via transdermal regional neuro-affective(TRNA) or regional neuro-affective (RNA) therapy via administration of adrug at the back of the neck at the hairline (BONATH). The drug isselected from, e.g., an anti-epileptic, an anxiolytic, a neuroleptic, ananti-psychotic, an analgesic, an anti-inflammatory, an anti-Parkinson'sdisease/syndrome drug, a sexual dysfunction drug, a drug for thetreatment of dystonia, a drug for the treatment of spastic conditions, adrug for the treatment of benign essential/familial tremor, a drug forthe treatment of tremor related to MS, a drug for the treatment ofchronic encepahalopathies, a drug for the treatment of congenital CNSdegeneration conditions/cerebral palsy, a drug for the treatment ofcerebellar degeneration syndromes, a drug for the treatment ofneuropathic and/or neurogenic pain, a drug for smoking cessation, a drugfor appetite suppression, a drug for neurodegenerative conditions, adrug for the treatment of multiple sclerosis, a drug for the treatmentof insomnia, a drug for the treatment of fatigue, a drug for thetreatment of vertigo, nausea and/or dizziness, a drug for the treatmentof writer's cramp and restless leg syndrome, a drug for the treatment ofADD/ADHD, and other drugs which can beneficially be administered at theback of the neck at the hairline in close proximity to and under or onthe area of skin above the brain stem to provide regionalneuro-affective therapy to the patient.

The invention is also directed to a topical formulation, comprising adrug selected from an anti-epileptic, an anxiolytic, a neuroleptic, ananti-psychotic, an analgesic, an anti-inflammatory, an anti-Parkinson'sdisease/syndrome drug, a sexual dysfunction drug, a drug for thetreatment of dystonia, a drug for the treatment of spastic conditions, adrug for the treatment of benign essential/familial tremor, a drug forthe treatment of tremor related to MS, a drug for the treatment ofchronic encepahalopathies, a drug for the treatment of congenital CNSdegeneration conditions/cerebral palsy, a drug for the treatment ofcerebellar degeneration syndromes, a drug for the treatment ofneuropathic and/or neurogenic pain, a drug for smoking cessation, a drugfor appetite suppression, a drug for neurodegenerative conditions, adrug for the treatment of multiple sclerosis, a drug for the treatmentof insomnia, a drug for the treatment of fatigue, a drug for thetreatment of vertigo, nausea and/or dizziness, a drug for the treatmentof writer's cramp and restless leg syndrome, a drug for the treatment ofADD/ADHD, and combinations of any of the foregoing, in a formulationsuitable for administration at the the back of the neck at the hairlinein close proximity to and under or on the area of skin above the brainstem of a human patient to provide regional neuro-affective therapy tothe patient. The topical formulation may be prepared as an immediate,controlled or sustained release formulation.

The drug formulations useful in the present invention may be in a formselected from a topical formulation (e.g, a cream, ointment or gel); atransdermal device; or an implantable or injectable formulation.

The invention is further directed to the use of a drug selected from thegroup consisting of anti-epileptic, an anxiolytic, a neuroleptic, ananti-psychotic, an analgesic, an anti-inflammatory, an anti-Parkinson'sdisease/syndrome drug, a sexual dysfunction drug, a drug for thetreatment of dystonia, a drug for the treatment of spastic conditions, adrug for the treatment of benign essential/familial tremor, a drug forthe treatment of tremor related to MS, a drug for the treatment ofchronic encepahalopathies, a drug for the treatment of congenital CNSdegeneration conditions/cerebral palsy, a drug for the treatment ofcerebellar degeneration syndromes, a drug for the treatment ofneuropathic and/or neurogenic pain, a drug for smoking cessation, a drugfor appetite suppression, a drug for neurodegenerative conditions, adrug for the treatment of multiple sclerosis, a drug for the treatmentof insomnia, a drug for the treatment of fatigue, a drug for thetreatment of vertigo, nausea and/or dizziness, a drug for the treatmentof writer's cramp and restless leg syndrome, a drug for the treatment ofADD/ADHD, in the preparation of a medicament for providing regionalneuro-affective therapy to a human patient, wherein the drug isadministered at the back of the neck at the hairline in close proximityto and under or on the area of skin above the brain stem to provideregional neuro-affective therapy to the patient.

In certain embodiments, the drug is applied to the posterior cervicalregion of the human in order to effect the brainstem afferentstimulation therapy. Most preferably, the topical formulation ortransdermal therapeutic system is applied to the back of the neckpreferably in close proximity to or on the area of skin above the brainstem.

In other embodiments, the drug is administered via implantation orinjection at the back of the neck at the hairline (BONATH). In suchembodiments, the therapy is accomplished via the availability of thedrug(s) at the free nerve endings under the epidermis. In suchembodiments, the drug may be incorporated into an implantation device ormay be incorporated into a carrier such as a gel or matrix that willprovide a prolonged release/effect of the dopamine agonist at the site.The carrier may be a hydrophilic or hydrophobic material, a colloidalmaterial, and may be in a state ranging from a viscous liquid to a solidpolymeric insert.

Certain embodiments of the invention are directed to a method oftreatment, comprising delivering a drug(s) through regionalneuro-affective therapy by application as a cream/gel or a sustainedrelease patch applied at the back of the neck at the hairline (BONATH),or via administration under the skin at the BONATH via an implantable orinjectable drug formulation or device.

In certain embodiments, the method further provides for atherapeutically effective treatment through transdermal regionalneuro-affective (TRNA) therapy by application of a drug(s) as acream/gel or a sustained release patch applied at the back of the neckat the hairline (BONATH) without the side-effects and the otherdraw-backs of the current injection method.

In certain embodiments, the drug is a dopamine agonist such asapomorphine (Apokyne, APO-go®), pramipexole (Mirapexin®), ropinirole(Requip®), bromocriptine (Parlodel®), cabergoline (Cabaser®, Dostinex®),pergolide (Permax®, Celance®) rotigotine (Neupro®), mixtures of any ofthe foregoing, or other dopamine agonists known to those skilled in theart.

In other embodiments, the drug is opioid such as morphine, codeine,dihydrocodeine, hydrocodone, hydromorphone, nicomorphine, oxycodone,oxymorphone, fentanyl, alphamethylfentanyl, alfentanil, sufentanil,remifentanil, carfentanyl, ohmefentanyl, thebaine, oripavine,diacetylmorphine (heroin), phenylpiperidines such as pethidine(meperidine) and ketobemidone, allylprodine, prodine, propoxyphene,dextropropoxyphene, dextromoramide, bezitramide, piritramide, methadone,dipipanone, levomethadyl Acetate (LAAM), loperamide, diphenoxylate,dezocine, pentazocine, phenazocine, buprenorphine, dihydroetorphine,etorphine, butorphanol, nalbuphine, levorphanol, levomethorphan,lefetamine, meptazinol, tilidine, tramadol, tapentadol, mixturesthereof, and the like.

In yet other embodiments, the drug is Tarpentadol (a centrally actingoral analgesic having two mechanisms of action combining mu-opioidreceptor agonism and norepinephrine reuptake inhibition).

Alternatively, the drug is an opioid antagonist, for example, naloxone,naltrexone, nalmefene, or mixtures thereof.

In yet other embodiments, the drug is a selective norepinephrinereuptake inhibitor, such as Atomoxetine (Strattera®), Mazindol(Mazanor®, Sanorex®), Nisoxetine (LY-94939), Reboxetine (Edrouax®,Vestra®), Viloxazine (Vivalan®), mixtures thereof, and the like.

In yet other embodiments, the drug is a benzodiazepine, such aslorazepam (Ativan®), diazepam (Valium®), clonazepam (Klonopin®),chlordiazepoxide (Librium®), alprazolam (Xanax®), mixtures thereof, andthe like. In other embodiments, the drug is a neuroleptic orpsychotropic such as chlorpromazine (Thorazine®), haloperidol (Haldol®),risperidone (Risperdal®), olanzapine (Zyprexa®) and quetiapine(Seroque®).

In yet other embodiments, the drug is a norepinephrine-dopamine reuptakeinhibitor (NDRI), such as Amineptine (Survectox®), Bupropion(Wellbutrin®, Zyban®), Dexmethylphenidate (Focalin®), Methylphenidate(Ritalin®, Concerta®), Nomifensine (Merital), mixtures thereof, and thelike.

In yet other embodiments, the drug is a serotonin-norepinephrinereuptake inhibitor (SNRI), such as Desvenlafaxine (Pristiq®), Duloxetine(Cymbalta®), Milnacipran (Ixel®, Savella®), Venlafaxine (Effexor®),mixtures thereof, and the like.

In yet other embodiments, the drug is a tricyclic antidepressant (TCA),such as Amitriptyline (Elavil), Butriptyline (Evadene®, Evadyne®),Clomipramine (Anafranil®), Desipramine (Norpramin®, Pertofrane®),Dosulepin (Prothiade®), Doxepin (Adapin®, Sinequan®), Imipramine(Tofranil®). Lofepramine (Feprapax®, Gamanil®, Lomont®), Nortriptyline(Aventyl®, Nortrilen®, Pamelor®), Protriptyline (Vivactil®),Trimipramine (Surmontil®), mixtures thereof, and the like.

In yet other embodiments, the drug is a tetracyclic antidepressant, suchas Ampxapine (Asendin®), Maprotiline (Ludiomil®), Mianserin (Tolvon®),mixtures thereof, and the like.

In yet other embodiments, the drug is an atypical antipsychotic, such asZiprasidone (Geodon®, Zeldox®), Nefazodone (Serzone®), and the like.

In yet other embodiments, the drug is an anti-epileptic drug such asValproic acid (Depacon®/Depakotc®), Leviteracetem (Keppra®), Lamotrigene(Lamictal®), Topiramate (Topamax®), Pregabalin (Lyrica®), Gabapentin(Neurontin®), Carbamazepine (Tegretol®), Oxcarbazepine (Trileptal®),Phenobarbital and other barbiturates, Tiagabine (Gabatril®), Retigabine™(Valeant Pharmaceuticals). Lacosamide™ (Schwarz Biosciences), andPerampanel™ (Eisai) are in development as anti-epileptics andneuromodulators for other associated neurological, pain, and psychiatricconditions, and thus are further examples of potentially useful drugs inthe present invention.

In yet other embodiments, the drug is an analgesic/anti-inflammatoryagent such as acetaminophen; prednisone, solumedrol, and other steroids;naproxen, aspirin, voltaren, ketoprofen, ibuprofen, and other NSAID's.

In yet other embodiments, the drug is an appetite suppressant, such asSibutramine (Meridia®, Reductil®), which is a centrally actingserotonin-norepinephrine reuptake inhibitor that is structurally relatedto amphetamines but having a distinct mechanism of action. Otherpotentially useful drugs for anti-obesity include Rimonabant(Acomplia®), substances related to amphetamine, such as phentermineand/or fenfluramine and/or dexfenfluramine, (the combination popularlyreferred to phen-fen) may also be useful in the treatments of thepresent invention. It is believed that the present method of treatmentwould avoid the potential heart value damage found with thesecombinations when administered orally.

For purposes of the present invention, a “topical formulation” includes,for example, ointments, creams, lotions, pastes, gels, etc., whichreleases one or more drugs (e.g., dopamine agonists) at a predeterminedrate over a defined period of time to a defined site of application.

For purposes of the present invention, an “injectable” formulationincludes, for example, an injectable solution, suspension, gel or thelike and may be in immediate release form or may provide a controlled orsustained release of the drug at the site of administration.

For purposes of the present invention, an “implantable” formulationincludes, for example, a solid, semisolid or liquid drug formulationwhich can be administered at the site of administration (e.g., BONATH)either via injection and/or via surgical implantation. The solid maycomprise microspheres, microcapsules, pellets, discs, and the like. Theimplantable formulations of the invention may provide a controlled orsustained release of the drug at the site of administration.

For purposes of the present invention, a“transdermal therapeutic system”is defined as a drug-containing device (including e.g., patch, disc,etc.) which releases one or more drugs at a predetermined rate over adefined period of time to a defined site of application.

For purposes of the present invention, “transdermal” delivery is thedelivery by passage ofa drug through the skin and into the bloodstream(“traditional” transdermal delivery) and is termed “transdermal systemicdrug delivery (TSD therapy).

For purposes of the present invention, the term “topical transdermaltherapy” is synonomous with the more accurately termed topical regionalneuro-affective therapy (or “TRNA therapy”). This term describesimportant aspects of this delivery method: topical, regional (nearbrainstem and cervical spinal cord), and affecting the free nerveendings of the afferent nervous system.

For purposes of the present invention “therapeutically effective” or“effective” amount is meant to be a nontoxic but sufficient amount of acompound to provide the desired therapeutic effect, e.g., avoidance ofthe onset of a migraine and or increased alleviation of the migraineand/or cluster headache. In the present case, for example, it is thedose of serotonin agonist that will be effective in relieving symptomsof the migraine or cluster headache. An “effective” amount of apermeation enhancer as used herein, for example, means an amount thatwill provide the desired increase in skin permeability and,correspondingly, the desired depth of penetration, rate ofadministration, and amount of drug to be delivered.

For purposes of the present invention, the term “delivers” when usedwith respect to the topical formulation or transdermal therapeuticsystem means that the formulation or system provides a mean relativerelease rate or flux of the drug out of the formulation or system andthrough the skin of the patient.

By “predetermined area of skin” is intended a defined area of intactunbroken living skin. In certain embodiments of the present invention,the predetermined area will be in the range of about 1 cm2 to about 100cm2, preferably in the range of about 10 cm2 to about 100 cm2, morepreferably in the range of about 20 cm2 to about 60 cm2. However, itwill be appreciated by those skilled in the art of topical delivery thatthe area of skin through which drug is administered may varysignificantly, depending on the formulation, dose, the application ofthe formulation, and the like.

“Penetration enhancement” or “permeation enhancement” for purposes ofthe present invention relates to an increase in the permeability of skinto a pharmacologically active agent, i.e., so as to increase the rate atwhich the drug permeates through the skin and enters the bloodstream.The enhanced permeation effected through the use of such enhancers canbe observed by measuring the rate of diffusion of drug through animal orhuman skin using a diffusion cell apparatus.

For purposes of the present invention, the “brainstem afferentstimulation therapy region” is defined as the skin region of the headand/or at the frontotemporal region and/or upper posterior cervicalarea. In certain preferred embodiments, the treatment area is the postcervical area in close proximity to the brain stem. Preferably this areais a relatively hairless area of the patient's head and/or neck.

For purposes of the present invention, the drug may be in the form ofthe base, or may be provided as a pharmaceutically acceptable salt(inorganic or organic) or complex. It may be in an optically pure formor a mixture of stereoisomers.

DETAILED DESCRIPTION

An important aspect of the benefits of “TRNA” or “RNA” BONATH” therapyin CNS drug delivery for brainstem related disorders lies in the anatomyof the region. The free nerve endings with receptors for theneuro-chemicals dopamine, serotonin, norepinephrine, and others arelocated just below the surface of the skin, easily assessable to drugscompounded in an appropriate dermal penetration enhancing medium andtopically applied to the skin.

An important component of the brainstem autonomic nervous system is the“flight or fight” (sympathetic) response responsible for protecting anindividual from danger. Programmed to act “automatically” withouttime-consuming thought, it results in physiological and emotionalmanifestations reflective of either fleeing from or fighting/confrontingperceived danger. Often, the difference between the two is not clearlydelineated, as in most situations, the response is mixed.

Norepinephrine (noradrenaline) and serotonin are considered theprincipal neurotransmitters involved with the sympathetic autonomicsystem “fight or flight” response. Dopamine and acetylcholine (primarilyaffects the parasympathetic system) also play roles. The collections ofneuronal nuclei responsible for the production of theseneurotransmitters reside in the brainstem. The locus ceruleous containsneurons which produce norepinephrine, the dorsal raphe is responsiblefor serotonin production, and the substantia nigra, for dopamine.Acetylcholine is produced in a more widespread fashion.

It is now widely accepted that mood disorders are related todysregulation of neurotransmitters—“brain chemical imbalance”. Drugtherapies are directed at “re-establishing neurochemical balance” in thebrain through the use of serotonin re-uptake inhibitors (SSRI's) andserotonin and norepinephrine re-uptake inhibitors (SNRI's). Althoughthese drugs are effective, they take several weeks to months to showsignificant benefit. Furthermore, their clinical effect is mostpronounced for the chronic symptoms related to depression and anxiety.They are ineffective or less effective than desired for the episodicacute symptoms of anxiety reactions and panic attacks which commonlyaccompany these chronic conditions. To this end, acute treatment forbreak-through episodes has been in the form of oral or injectibleanxiolytics, depending on severity of symptoms. Commonly used drugs arethe benzodiazepines: lorazepam (Ativan), diazepam (Valium), clonazepam(Klonopin), chlordiazepoxide (Librium), and alprazolam (Xanax). Forparticularly severe symptoms, neuroleptics and psychotropics may also beused: chlorpromazine (Thorazine), haloperidol (Haldol), risperidone(Risperdal), olanzapine (Zyprexa) and quetiapine (Seroquel).

Oral and injectible anxiolytics and neuroleptics/psychtropics must relyon systemic blood (and therefore, blood levels) for eventual effect onthe brain. This is associated with undesirable systemic side-effects,partieularly fatigue and lethargy acutely post-dose. With chronic use,psychological dependency, tardive dyskinesia, Parkinsonism, obesity, andinsulin resistance may be encountered. With oral preparations, there isdelay (½ to several hours) before significant clinical effect. In somesituations, this degree of delay is unacceptable as profound clinicaldecompensation may result. An example is a panic attack in a predisposedindividual that leads to a psychotic breakdown or anon-epileptic/psychogenic seizure. The clinical consequence for such anaffected individual is significant. There is also the additionalfinancial expense of an emergency room visit or hospitalization.

Mood changes with symptoms of anxiousness, sadness, and elation are partof the human experience. These normal emotions oflife become problematicwhen they become severe, persistent, and interfere with functionalability. It is at this point that medical intervention needs to beconsidered. Whether one gets to the point of requiring medical therapyis dependent on several factors. One is the innate nature of theperson's make-up: how they are “wired and programmed” to deal with theissues of life. Some of this relates to family history, growth anddevelopment pre and post-natally (intra-uterine insult and birthtrauma), and one's basic emotional and philosophical outlook. Theexternal factors consist of stressors impinging on the individual:relational, physical (illness and disability), financial, work-related,etc. In this regard, it is not just the degree of stress that isimportant but also the length of time associated. Certain life eventsare universally stressful for all individuals: death of a loved one,divorce, losing a job. Still, how these events specifically impact anindividual depends on one's coping mechanisms and the specifics of theevent for that individual.

Psychologists have devised a “life crisis unit” scale (LCU's) foremotionally significant life stress events. The scale ranges from 0 to100, with the more emotionally significant events in the higher range.It has been determined that if an individual accumulates 250-300 pointsover a relatively short period, 3-4 months, they are at risk for anervous breakdown and/or significant physical illness. Accordingly,individuals at risk from innate make-up are particularly prone todecompensation when such extermal stress events come in to their lives.These are the people who experience frequent panic attacks and emotionalbreakdowns. Their lives are significantly disrupted and they may becomeemotionally disabled.

These individuals require prompt recognition with the institution ofearly, appropriate therapy. Untreated, they are prone to the phenomenonof pervasive dysfunction from persistent neuronalhyper-excitability/dysfunction. This, in turn may result inre-programming of neural circuits with accompanying permanentpsychological and behavioral changes. This progression of events is akinto the process of “kindling” which occurs in epileptic conditions:untreated or inadequately treated seizure foci spread to other areas ofthe brain and become increasingly resistant to therapy. The new foci ofneuronal hyper-excitability may be adjacent to the original or crossover the corpus callosum as a “mirror focus”.

A similar phenomenon occurs in migraine, a condition with increasedpropensity to neuronal hyper-excitability in the brainstem withperipheral and cortical sensitivity to triggers. If treatment isrendered late or inadequately, there is a greater likelihood for moresevere and persistent symptoms. In this regard, young migraneurs alsoneed to be identified early and treated to reduce life-long disabilityfrom chronic, severe migraines.

The “fight or flight” sympathetic system response, interpreted asstress, is in the most basic sense, a fear-based reaction: fear of theuncertainty related to significant life stress events. The experiencedfear may be real or perceived but the effect is the same: perceiveddanger as the individual's sense of control and stability is threatened.Interestingly, as the LCU scale suggests, the more emotionallysignificant the event, the more likely it results in a stress reaction.Even “positive” stress (job promotion with increased responsibilities)may have negative effects similar to the negative event of being firedfrom a job. In this respect, “stress” may be defined as: any change thatsignificantly alters one's status quo and questions the individual'ssense of security and stability physically, emotionally, orrelationally.

As the sympathetic nervous system serves to protect the individual, itis easy to understand that it is also intimately involved with painperception in addition to the psychological response. In fact, the twosystems go hand-in-hand: the more severe the perceived pain, the greaterthe emotional toll and likelihood for depression; and vice-versa, adepressed individual perceives pain more acutely than one who is not. Itis also recognized that “emotional” pain (heartbreak) disrupts brainstemfunction and more significantly affects the individual than physicalpain such as that associated with a heart attack or a broken arm. Theemotions of fear, betrayal, and abandonment may be attached to theformer. The neuro-transmitters norepinephrine and serotonin have bothbeen recognized to play significant roles in the human psychological andpain response. Drugs which modulate, increase, and balance the levels ofthese two brain chemicals have been approved for both mood and painsyndromes.

The SNRI's duloxitine (Cymbalta®) and venlafaxine (Effexor®), as well asthe older tricyclic antidepressants, such as amytriptilene (Elavil®),have shown benefit for depression and for neuropathic pain, with orwithout associated mood dysfunction.

There have also recently come on the scene, drugs in the category of“neuromodulators” which treat neurochemical imbalance and dysfunctionsyndromes indirectly. Gabapentin (Neurontin®) and pregabalin (Lyrica®)are specific calcium channel modulators which influence serotonin andnorepinephrine release at their respective receptors. They are indicatedfor such diverse and seemingly different conditions as: focal onsetseizures, post-herpetic neuralgia, diabetic peripheral neuropathy,fibromyalgia, anxiety, and drug withdrawal syndromes. The commonality inthese conditions is that there has occurred some component of neurologicinjury with resultant persistent neuronal hyper-excitability anddysfunction. The abnormally increased activity of these neuronalpopulations in turn results in neurochemical imbalance. Theseneuro-modulating drugs act to suppress such activity and re-establishneurotransmitter equilibrium. The resultant specific symptom reductionor resolution depends on the specific location and functions of theaffected neuronal population.

Many anti-epileptic drugs have also been found of benefit inpsychological conditions manifesting significant fluctuations and swingsin mood. Bipolar affective disorder (manic-depressive disorder) is sucha disorder, alluding there is likely neuronal hyper-excitabilityinvolved with these conditions. Thus, it is the specific population ofneurons and their connections which determine the symptoms experiencedby the patient. The seizure drugs valproic acid (Depakote®) andlamotrigene (Lamictal®) are both indicated for bipolar affectivedisorder in addition to their initial indications for epilepsy.Anti-epileptic drugs, together with anti-depressants and anxiolytics areused in the treatment of “non-epileptic”/psychogenic seizures, aninvoluntary, conversion reaction disorder with significant psychologicaldisability. The anti-epileptics Depakote and Topamax are also FDAapproved for migraine headache prophylaxis, suggesting the associationof hyper-excitable neuronal populations requiring stabilization withthis condition.

Approved medical therapy for Parkinson's disease (PD) in the UnitedStates is limited to oral and subcutaneous (sub-Q) injection. Thetablet, in ordinary or oral-dissolving form (ODT), is used to deliverlevodopa to the central nervous system (CNS) in combination withcarbidopa (Sinemet®) or with a COMT inhibitor (Comtan®); dopamineagonists, MAO inhibitors, COMT inhibitors, and other agents also use theoral route. Apomorphine, as sub-Q injection (Apokyn®), is approved forthe acute treatment of episodes of hypomobility/off-periods associatedwith PD. In Europe, apomorphine is also given by intra-peritoneal pump.All current treatment modalities are considered “systemic” in thatultimate therapeutic effect relies on blood flow: first the generalcirculation, then, the cerebral blood, to reach target sites in CNS.This also holds true for the transdermal dopamine agonist (rotigotine)patch, Ncupro®, which, applied to the skin, required absorption intosub-Q vessels for eventual delivery to CNS. Neupro was removed from theU.S. market after technical problems with crystallization within thepatch matrix but remains available in Europe. Studies are underway toreintroduce it in the U.S.

The widespread presence of active drug in systemic and cerebral blood islikely the primary source of side-effects associated with PD drugs. Asstimulation of dopamine receptors and other neuro-chemical effects occurat regions other than those targeted, unwanted drug effects occur.Further, with reliance on blood flow for therapeutic effect,idiosyncrasies in the cardiovascular and cerebrovascular systems need tobe considered. Heart disease and atherosclerosis, both common in elderlyPD patients, can significantly affect systemic drug delivery. With oraldelivery of PD medications, gastrointestinal (GI), disease affecting GItransit, absorption, and hepatic metabolism are concerns.

Systemic delivery of PD drugs also raises the concern of“non-physiologic effects” as active drug is delivered to “downstream”neuro-anatomical structures in advance of those “upstream.” Within thedopaminergic system, normal physiological sequence of neuro-chemicalflow and effect is from brainstem (substantia nigra) to striatum(caudate and putamen) by ascending nigra-striatal pathways. Accordingly,therapeutic effect would seem best realized when PD drug effect followsthe same neuro-physiological sequence. This may particularly hold truefor dopamine precursors and agonists. The long term dopamine therapyeffects of “receptor hypersensitivity,” manifest as motor complicationsand “on-off phenomena,” may be the consequence of persistent,fluctuating, non-physiologic “downstream” dopamine receptor stimulation.

All currently approved therapies for the conditions described abovereach the central nervous system through the systemic circulation.Cerebral blood flow to brainstem structures is through the posteriorcirculation, via the vertebral and basilar arteries and their branches.In view of the undesirable side-effects associated with this form ofdrug delivery to the brain, the present invention is directed in part tothe targeted regional delivery to the brainstem.

To understand the concept of “peripheral de-afferentation” as it appliesto the brainstem and how topical drug delivery to the back of the neckworks requires a review of the neuro-anatomy and the neuro-physiology ofthe region. As indicated above, this area of the nervous system is verycomplicated, compact and highly inter-active and inter-related.

The Trigeminal Nerve System is a component of the brainstem whichcoordinates pain input from the face, head, and the back of the neck. Assuch, it intimately influences the production of other symptomsassociated with syndromes attributed to dysfunction within thetrigeminal complex. These include the photophobia, phonophobia, nausea,anxiety, allodynia, and other focal sensory symptoms which may accompanya migraine attack. Similarly, episodes of trigeminal neuralgia (ticdouloreux) frequently involve significant affective (emotional) andvisceral components. Because of proximity and connections to otherstructures in the brainstem, abnormalities of temperature regulation,thirst, alertness, and mood are common. Some of these symptoms may be asequally disabling as the head and face pain.

In addition to receiving pain and sensory (afferent) input from theface, nasal and para-nasal sinuses, the teeth, scalp, the dura of theanterior and middle cranial fossa, the trigeminal system receivessimilar input from the soft tissues of the posterior cervical region.The free nerve endings in the back of the neck are just below thesurface of the skin, easily accessible to topically delivered drugsformulated in an appropriate dermal penetration enhancing compoundingmedium. The free nerve endings, via the small un-myelinated andmyelinated “C-fibers” (pain fibers) carry pain impulses through afferentsensory nerves back to the Trigeminal Nucleus Caudalis (TNC). TNC is thepain processing center extending from the pons through the entire extentof the brainstem to the upper cervical spinal cord. After synapsing atthe thalamus, pain impulses from TNC travel to the somatosensory cortex,where pain is perceived.

As providing important afferent input to the brain, the trigeminalsystem also receives afferent input from the rest of the body. Affarentinput is defined as any neural impulses coming back to the brain fromthe body. As such it provides information to the brain for processingand interpretation: pain, sensation, autonomic functions. Efferentoutput, on the other hand, consists of impulses originating in thecentral nervous system (brain, brainstem, and spinal cord) flowing tothe body for function: movement, response, action.

The vagus nerve includes both efferent and afferent fibers and isattached to the lower brainstem (medulla oblongata) via 8-10 radicles.The afferent fibers arise in the jugular and the nodose vagus ganglia.The somatic afferent fibers terminate in the nucleus of thetrigemino-spinal tract (TNC). Both the jugular and the nodose gangliaare connected with the superior cervical sympathetic gangion throughinter-communicating rami. The superior cervical sympathetic ganglion islocated between the internal carotid artery and the jugular vein on theventral aspects of the transverse processes of the 2nd, 3rd, and the 4thcervical vertebrae. It is the largest of the sympathetic trunk ganglia.

Sympathetic roots arising from the ganglion join the 1st and the 2ndcervical nerves; frequently the 3rd, and occasionally, the 4th. Inaddition to nerve fibers which extend rostrally from the superiorcervical sympathetic ganglion, the sympathetic innervation of the headincludes fibers which join the plexi on the common carotid and thevertebrtal arteries. The one on the vertebral artery is continuous withthe plexus on the basilar artery. Rami derived from the internal carotidplexus join the trigeminal nerve and the cavernous plexus in addition tothe other structures such as the abducens and deep petrosal nerves. Fromthe cavernous plexus, located in the middle cranial fossa, sympatheticfibers join the oculomotor, trochlear, and the ophthalmic nerves. Fibersfrom the plexus also accompany blood vessels into the hypophysis.

The spheno-palatine gangion, located in the pterygo-palatine fossa,receives sypmpathetic fibers from the face with rami distributed to themucous membranes of the nares, mouth, the pharynx, and some orbitalstructures.

From the above, it is clear that cervical nerve function is intimatelyrelated to vagal afferents and afferents from the face, head, and thedura of cranial fossae associated with migraine and other head and facepain syndromes.

It has been long reported that vagal nerve stimulation (VNS) in the neckdown-regulates abnormal discharges from epileptic foci and treatsseizures. VNS is now approved as adjunct to medical therapy in certainforms of intractable epilepsy. It is also of benefit in severedepression resistant to traditional drug therapy. Studies with VNS inmigraine, anxiety, and fibromyalgia have been underway and have shownpreliminary promise in benefit.

The mechanism of action appears to be the down-regulation ofhyper-excitable, dysfunctional neuronal systems by increased inhibitoryinput to brainstem and associated connections through stimulation of theafferent system. Affarent stimulation, by feed-back through TNC, causesreduction in efferent output from the brainstem, resulting in resolutionof clinical symptoms through down-regulation of hyper-active neuronalstructures.

In the same way the electrical stimulation of VNS accomplishes itseffect on the brainstem, topical drug therapy to the posterior cervicalregion, in close proximity to the brainstem and its afferent inputs, istheorized to provide effect for the conditions mentioned above. Thus,drugs proved of benefit for these disorders, show improved efficacy withdiminished side-effects if delivered in the manner suggested. Otherdrugs being developed for these conditions should similarly beconsidered for such delivery.

It is hypothesized that benefits of the present method of topical drugdelivery of central nervous system (CNS) active drugs lies in the factthat drug concentration gradients and blood flow factors are un-involvedin the therapeutic process. In contrast, the proposed delivery operatesthrough direct nerve connections between skin peripheral nerves at theback of the neck at the hairline (BONATH) and brainstem structures.Active drug compounded in an appropriate “dermal penetration enhancing”medium topically applied to the skin at the back of neck has effect onthe free nerve endings of peripheral nerves located immediately belowthe skin surface. Receptors to dopamine, serotonin, norepinephrine, andother neuro-transmitters/neuro-chemicals involved with neuraltransmission are located on these free nerve endings. Therefore,topically applied drug has near immediate therapeutic effect as directneural impulses are involved—the concept of brainstem afferentstimulation through topical regional neuro-affective (TRNA) therapy. Allprior art and methods of drug delivery to the CNS have involved bloodflow and therapeutic drug blood level requirements. The proposed methoddoes not require such, which are the source of undesirable systemic andCNS side-effects. The presently proposed drug delivery process operateson the principle of an electrical capacitor whereas the prior relied onthose fluid dynamics and reservoir principles.

The factors which determine the success of TRNA therapy include: thedrug being considered, the compounding substance (surfactant/dermalpenetration enhancer), the disease process, and the location ofapplication. For migraine, face and head pain syndromes, Parkinson'sdisease, and other conditions relying on afferent input to or throughthe cervical cord and brainstem, it is believed that the currentlyproposed method is ideal. The free nerve endings in the skin at the backof the neck are important components of the cervical nerves with richconnections to the trigeminal, vagal, and sympathetic systemscommunicating with brainstem structures and other components of thecentral nervous system. These are the areas pain and other symptomsrelated to neuro-chemical release are processed and perceived.

The skin at the upper part of the back of the neck, at the hairline, isinnervated by (supplied by nerves) the cervical nerve roots C 1-3 thatare also part of the Trigeminal Nerve system of the brainstem. Thesecervical nerves (the wires) have their cell bodies (their generators)within the Nucleus Caudalis (Spinal Nucleus) of the Trigeminal Nerve inthe cervical spinal cord and the brainstem. Accordingly, they havedirect neural connections with brainstem processing areas. At the sametime, the peripheral nerve receptor sites for these nerves, the freenerve endings, reside under the skin surface at the back of the neck.The nerves in the soft tissues of the back of the neck, representing theC1, C2, and C3 segments of the cervical spinal cord are unique in thatthey have intimate connections with pathways directly affectingbrainstem and autonomic system function. There are direct connectionswith the Trigeminal Nerve system of the brainstem which provides forpain and other sensory input and interpretation from the head, face,sinus cavities, the dural covering of the brain, and the back of theneck. There are also connections with the vagus nerve and thesympathetic nervous system through the sympathetic ganglia. Thus, it isthrough these connections, which are nowhere else in the body asinter-related or at such close proximity to the surface of the humanskin, that the potential for the delivery of CNS acting drugs throughthe skin at the back of the neck (BONATH) is realized. Finally, skin isembryologically derived from neuro-ectoderm which is also responsiblefor the formation of the brain and other aspects of the CNS. Thus, thenerves in the human skin have a particularly direct relationship withthese structures. This provides for the efficacy noted with TRN BONATHtherapy. At the same time, systemic and other CNS side-effects arereduced or avoided. Thus, drugs topically applied to the skin in thisregion have ready access to brainstem and other CNS structures withoutthe requirement of drug in the bloodstream reaching target sites.

In addition to the upper cervical nerves having direct relation to theTrigeminal Nerve System, they also contribute to the CervicalSympathetic Ganglia and the Vagal Nerve Systems through directconnections. These latter two systems provide some of the mostsignificant affarent feed-back to the brainstem and other portions ofthe CNS from the rest of the body. This allows for additional brainstemaffarent stimulation potential through TRNA therapy at the back of theneck. Although skin at other areas of the face and head have eventualneural feed-back to the brainstem, the intimate connections to afferentfeed-back systems are lacking.

To understand the concept of peripheral afferent stimulation (or“de-afferentation”) as it applies to brainstem afferent stimulation andhow topical drug delivery to the back of the neck works requires areview of the neuro-anatomy and the neuro-physiology of the region. Asindicated above, this area of the nervous system is very complicated,compact and highly inter-active and inter-related.

The Trigeminal Nerve System is a component of the brainstem whichcoordinates pain input from the face, head, and the back of the neck. Assuch, it intimately influences the production of other symptomsassociated with syndromes attributed to dysfunction within thetrigeminal complex. These include the photophobia, phonophobia, nausea,anxiety, allodynia, and other focal sensory symptoms which may accompanya migraine attack. Similarly, episodes of trigeminal neuralgia (ticdouloreux) frequently involve significant affective (emotional) andvisceral components. Because of proximity and connections to otherstructures in the brainstem, abnormalities of temperature regulation,thirst, alertness, and mood are common. Some of these symptoms may be asequally disabling as the head and face pain.

In addition to receiving pain and sensory (afferent) input from theface, nasal and para-nasal sinuses, the teeth, scalp, the dura of theanterior and middle cranial fossa, the trigeminal system receivessimilar input from the soft tissues of the posterior cervical region.The free nerve endings in the back of the neck are just below thesurface of the skin, easily accessible to topically delivered drugsformulated in an appropriate dermnal penetration enhancing compoundingmedium. The free nerve endings, via the small un-myelinated andmyelinated “C-fibers” (pain fibers) carry pain impulses through afferentsensory nerves back to the Trigeminal Nucleus Caudalis (TNC). TNC is thepain processing center extending from the pons through the entire extentof the brainstem to the upper cervical spinal cord. After synapsing atthe thalamus, pain impulses from TNC travel to the somatosensory cortex,where pain is perceived.

As providing important afferent input to the brain, the trigeminalsystem also receives afferent input from the rest of the body. Afferentinput is defined as neural impulses coming back to the brain from thebody. As such, it provides information to the brain for processing andinterpretation: of pain, sensation and other perception, motor, andautonomic functions. Efferent output, on the other hand, consists ofimpulses originating in the central nervous system (brain, brainstem,and spinal cord) flowing to the body for function: movement, response,action.

The nerves in the soft tissues of the back of the neck, representing theC1, C2, and C3 segments of the cervical spinal cord are unique in thatthey have intimate connections with pathways directly affectingbrainstem and autonomic system function. The brainstem represents theprimary neural relay and processing center of the body. In the human, itis the size of the thumb and contains the most dense and complicatednetwork of neural connections any where. It functions to relay allneural impulses from the brain to the body (efferent output) as well asreceive them back from the body to the CNS for processing (afferentinput).

There are direct connections between the nerves in the skin at the backof the neck and the Trigeminal Nerve system of the brainstem, whichprovides pain and sensory input and processing from the head, face,sinus cavities, and the dural covering of the brain. There also existafferent connections with the vagus nerve and the sympathetic nervoussystem through the sympathetic ganglia. It is through these connections,which are nowhere else in the body as inter-related or at such closeproximity to the surface of the human skin as at the back of the upperneck (BONATH), that the potential for the delivery of CNS active drugsthrough TRNA therapy is realized. As providing important afferent inputto the brain, the trigeminal system also receives afferents from therest of the body.

The vagus nerve includes both efferent and afferent fibers and isattached to the lower brainstem (medulla oblongata) via 8-10 radicles.The afferent fibers arise in the jugular and the nodose vagus ganglia.The somatic afferent fibers terminate in the nucleus of thetrigemino-spinal tract (TNC). Both the jugular and the nodose gangliaare connected with the superior cervical sympathetic gangion throughinter-communicating rami. The superior cervical sympathetic ganglion islocated between the internal carotid artery and the jugular vein on theventral aspects of the transverse processes of the 2^(nd), 3^(rd), andthe 4^(th) cervical vertebrae. It is the largest of the sympathetictrunk ganglia.

Sympathetic roots arising from the ganglion join the 1^(st) and the2^(nd) cervical nerves; frequently the 3^(rd), and occasionally, the4^(th). In addition to nerve fibers which extend rostrally from thesuperior cervical sympathetic ganglion, the sympathetic innervation ofthe head includes fibers which join the plexi on the common carotid andthe vertebrtal arteries. The one on the vertebral artery is continuouswith the plexus on the basilar artery. Rami derived from the internalcarotid plexus join the trigeminal nerve and the cavernous plexus inaddition to the other structures such as the abducens and deep petrosalnerves. From the cavernous plexus, located in the middle cranial fossa,sympathetic fibers join the oculomotor, trochlear, and the ophthalmicnerves. Fibers from the plexus also accompany blood vessels into thehypophysis (pituitary gland). The spheno-palatine gangion, located inthe pterygo-palatine fossa, receives sympathetic fibers from the facewith rami distributed to the mucous membranes of the nares, mouth, thepharynx, and some orbital structures.

From the above, it is clear that upper cervical (C1-4) nerve functionwith peripheral nerve free nerve endings in the skin at the back of theneck (BONATH) is intimately related to vagus nerve afferents andafferents from the face, head, and the dura of cranial fossae throughthe trigeminal nerve. These, in turn, provide feedback to the brainstemand other CNS structures for nerve signal processing.

It has been long reported that vagal nerve stimulation (VNS) in the neckdown-regulates abnormal discharges from epileptic foci and treatsseizures. VNS is now approved as adjunct to medical therapy in certainforms of intractable epilepsy. It is also of benefit in severedepression resistant to traditional drug therapy. Studies with VNS inmigraine, anxiety, and fibromyalgia have been underway and have shownpreliminary promise in benefit.

The mechanism of action appears to be the down-regulation ofhyper-excitable, dysfunctional neuronal systems by increased inhibitoryinput to brainstem and associated connections through stimulation of theafferent system. Affarent stimulation, by feed-back through TNC, causesreduction in efferent output from the brainstem, resulting in resolutionof clinical symptoms through down-regulation of hyper-active neuronalstructures.

In the same way the electrical stimulation of VNS accomplishes itseffect on the brainstem, topical drug therapy to the posterior cervicalregion, in close proximity to the brainstem and its afferent inputs, istheorized to provide effect for the conditions mentioned above. Thus,drugs proved of benefit for these disorders, show improved efficacy withdiminished side-effects if delivered in the manner suggested. Otherdrugs being developed for these conditions should similarly beconsidered for such delivery.

The question arises then: does TRNA therapy work with drug applicationto the forehead, face, or other regions of the head. The answer isperhaps—in some disease states such as migraine and face pain; but, notas effective and efficient as at the back of the neck at the hairline,BONATH. Free nerve endings are also present at these other locations butthe distance back to involved brainstem structures is greater and thereis not the added advantage of rich afferent neural connections to thetrigeminal, vagal, and sympathetic nerve systems which are associatedwith the posterior cervical region.

“TRNA BONATH” delivery differs from traditional therapy (whether oral,injection, nasal spray, inhalation, or rectal) in that it has noreliance on the systemic or cerebral blood flow. Nor does it requiretherapeutic blood levels of drug. These latter factors are responsiblefor systemic and CNS side-effects as drug is delivered to areas notintended to be affected in the therapeutic process. Transdermal systemicdelivery by patch, although similarly applied to the skin as in TRNABONATH therapy, differs significantly in its reliance on a drugconcentration gradient for absorption into, the systemic capillary andvenous blood. TRNA therapy is unaffected by dermal vessels or systemicblood flow. It relies solely on the function of the free nerve endingsof cutaneous nerves and their connections at the point of application ofcompounded drug.

“Traditional” transdermal drug delivery by patch and TRNA are both“transdermal” in that in both, drug penetrates the skin (epidermis) foreventual clinical effect. The difference lies in the fact that in“traditional” transdermal patch therapy, drug enters the systemiccirculation through a concentration gradient and establishes atherapeutic drug blood level. Although measuring a blood level givesassurance drug is being taken or delivered systemically, allowing forchecking compliance, it is also the source of undesirable side-effectsand drug interactions. Of necessity, with systemic transdermal patchtherapy, drug applied to the skin surface must be absorbed through thesmall vessels in the dermis for eventual presence in the systemic venousblood for measurement of drug level. With the proposed TRNA therapy,drug need only be available at the free nerve endings under theepidermis. No concentration gradients or systemic blood levels arenecessary. Drug delivery is unaffected by cardiac output or cerebralblood flow factors. Of significance, persons afflicted with Parkinson'sdisease are typically elderly with concomitant cardiac and cerebralvascular disease.

Thus, in certain embodiments, the methods and formulations of theinvention deliver an amount of drug (e.g., dopamine agonist) in the TRNAtherapy that would provide sub-therapeutic plasma levels if administeredorally, but which is therapeutically effective when administered viaTRNA therapy at the BONATH.

It is hypothesized by the inventor that a principal reason TRNA therapyis rapid in the onset of clinical effect (e.g., less than about 10minutes for migraine with topical sumatriptan and less than about 15minutes for Parkinson's disease with topical apomorphine) is that itoperates through an “electro-chemical” process. Active drug compoundedin an appropriate dermal penetration enhancing medium acts at free nerveendings, changing the neurochemistry of receptors at the neural synapse:apomorphine (dopamine and norepinephrine agonist), increasing dopamineand norepinephrine levels and improving neural transmission. After apoint of receptor stimulation, neural (electrical) impulses aregenerated back to neuronal cell bodies residing in the spinal cord andbrainstem: “afferent feed-back”. The nervous system functions throughneurons generating electrical impulses and the release ofneurochemicals/neuro-transmitters (serotonin, norepinephrine, dopamine,and acetylcholine, being the major ones) at neural receptor sites called“synaptic clefts”. Accordingly, the process in TRNA therapy may beconsidered analogous to an electrical capacitor discharging to perform afunction, such as turning on a light switch. Viewed from thisperspective, the rapid onset of clinical effect observed in TRNA therapymakes sense.

It is further hypothesized that via the use of TRNA therapy, thedopamine stimulation of receptors in the Nigra-striatal System isphysiological and down-stream: from the cutaneous free nerve-endings tothe cervical cord, to the brainstem and substantia nigra; then, viaascending nigra-striatal connections to the dopamine receptors withinthe caudate and putamen. With systemic (oral, injection, or patch) thedown-stream anatomical regions (caudate and putamen) may be stimulatedin advance of or at the same time as the upstream (brainstem)components. The inventor believes that much of the chronic motorcomplications of dopamine therapy are the result of this phenomenon—theresult of “dopamine receptor hypersensitivity”. This complication isbelieved to be avoided, and in fact, alleviated through TRNA dopaminedelivery, in which it is believed that the dopamine and otherneurochemical effects are physiological and flow in the direction andmanner in which they were intended—and therefore, most effective.

Alternatively, transdermal systemic patch delivery operates on theprinciples of chemical gradients and fluid dynamics. These processeshave variability and inherent idiosyncrasies, fluctuating heart functionas a pump for blood flow being one. Thus, despite the advantage ofmeasurable drug levels, a more circuitous route with slower clinicaleffect is observed. This makes systemic transdermal patch deliveryinappropriate for acute therapy.

Alternatively, rapid as well as prolonged clinical effect may beachieved by a sustained-release dermal system employing the principlesof TRNA therapy through patch application at the skin at the back of theneck at the hairline (BONATH). BONATH refers to the specific site oftopical drug application necessary for clinical effect in TRNA therapy.The location is critical in TRNA therapy, whereas, with the transdermalsystemic patch, location is irrelevant. The uniqueness of thisparticular area of the human anatomy which allows this-delivery methodto work is discussed below.

Alternatively, TSD therapy, the traditional transdermal systemicdelivery, operates on the principles of chemical gradients and fluiddynamics. These processes have associated inherent idiosyncrasies andvariabilities; heart function as a pump for blood flow being one.Accordingly, despite the advantage of measurable drug levels,traditional transdermal systemic delivery involves a more circuitousroute with slower clinical effect.

Rapid as well as prolonged clinical effect may be achieved by asustained-release patch placed at the same anatomical site, BONATH.

One skilled in the art having the benefit of the information containedherein will appreciate that there are many classes of drugs which wouldbe useful for topical brainstem de-afferentation therepy. These classesof drugs include, but are not limited to:

1. Anti-Epileptic drugs: Examples include Valproic acid(Depacon®/Depakot®), Leviteracetem (Keppra®), Lamotrigene (Lamictal®),Topiramate (Topama®), Pregabalin (Lyrica®), Gabapentin (Neurontin®),Carbamazepine (Tegretol®), Oxcarbazepine (Trileptal®), Phenobarbital andother barbiturates, Tiagabine (Gabatril®), Retigabine™ (ValeantPharmaceuticals), Lacosamide® (Schwarz Biosciences), and Perampanel®(Eisai) are in development as anti-epileptics and neuromodulators forother associated neurological, pain, and psychiatric conditions.2. Anxiolytic drugs: Benzodiazepines: Examples include lorazepam(Ativan®), diazepam (Valium®), clonazepam (Klonopin®), chlordiazepoxide(Librium®), and alprazolam (Xanax®).3. Neuroleptics/Anti-Psychotic drugs: Examples include chlorpromazine(Thorazine®), haloperidol (Haldol®), risperidone (Risperdal®),olanzapine (Zyprexa®) and quetiapine (Seroquel®).4. Analgesics/Anti-Inflammatory drugs: Examples include prednisone,solumedrol, and other steroids, naproxen, aspirin, acetaminophen,voltaren, ketoprofen, ibuprofen, other NSAID's.5. Parkinson's Disease/Similar or Related Syndrome drugs: Examplesinclude dopamine agonists such as apomorphine.6. Sexual Dysfunction drugs: Examples include dopamine agonists such asapomorphine.7. Dystonia (cervical and otherwise), which sometimes occur inconjunction with spasmodic torticollis and spastic conditions: Examplesof drugs include dopamine agonists such as apomorphine.8. Benign essential/familial tremor, tremor related to MS, chronicencepahalopathies such as from stroke or head injuries, congenital CNSdegeneration conditions/cerebral palsy, cerebellar degenerationsyndromes, and spasicity conditions from the above: Examples of drugsinclude dopamine agonists such as apomorphine.9. Neuropathic/Neurogenic pain drugs: Examples include carbamazepine,gabapentin, topiramate, zonisamide, phenytoin, desipramine,amitriptyline, imipramine, doxepin, protriptyline, pentoxifylline, andhydroxyzine.10. Smoking Cessation drugs: Examples include drugs such as varenicline.11. Appetite Suppressant drugs: Examples include drugs such asSibutramine.12. Neurodegenerative Diseases: Examples include drugs such asAricept/donepezil, Exelon/rivastigmine, Reminyl/Razadyne/galantamine,and Namenda/memantine and their naturally occurring counterparts, aswell as NMDA antagonists.13. Multiple Sclerosis (MS): Examples include drugs such as4-aminopyridine.14. Insomnia: Examples include drugs such as zolpidem.15. Fatigue: Examples include drugs such as pemoline and Modafinil.16. Vertigo, Nausea and/or Dizziness: Examples include drugs such as asmeclizine, dimenhydrinate, prochlorperazine, scopolamine anddiphenhydramine.17. Writer's cramp and restless leg syndrome: Examples include dopamineagonists such as apomorphine.18. ADD/ADHD: Examples include drugs such as lisdexamfetamine,methylphenidate.

In general, the formulations and methods described herein are useful forthe treatment ofneuronal hyperexcitability and neurochemical dysfunctionsyndromes and the drug may be, e.g., an anti-epileptic, an anxiolytic, aneuroleptic, an anti-psychotic, an analgesic, an anti-inflammatory, ananti-Parkinson's disease/syndrome drug, a sexual dysfunction drug, adrug for the treatment of dystonia, a drug for the treatment of spasticconditions, a drug for the treatment of benign essential/familialtremor, a drug for the treatment of tremor related to MS, a drug for thetreatment of chronic encepahalopathies, a drug for the treatment ofcongenital CNS degeneration conditions/cerebral palsy, a drug for thetreatment of cerebellar degeneration syndromes, a drug for the treatmentof neuropathic and/or neurogenic pain, a drug for smoking cessation, adrug for appetite suppression, a drug for neurodegenerative conditions,a drug for the treatment of multiple sclerosis, a drug for the treatmentof insomnia, a drug for the treatment of fatigue, a drug for thetreatment of vertigo, nausea and/or dizziness, a drug for the treatmentof writer's cramp and restless leg syndrome, a drug for the treatment ofADD/ADHD, and other drugs which can beneficially be administered at thethe back of the neck at the hairline in close proximity to and under oron the area of skin above the brain stem to provide regionalneuro-affective therapy to the patient.

In certain embodiments, the drug is a dopamine agonist such asapomorphine (Apokyn®, APO-go®), pramipexole (Mirapexin®), ropinirole(Requip®), bromocriptine (Parlodel®), cabergoline (Cabaser®, Dostinex®),pergolide (Pernmax®, Celance®) rotigotine (Neupro®), mixtures of any ofthe foregoing, or other dopamine agonists known to those skilled in theart. One skilled in the art will appreciate that dopamine agonists otherthan apomorphine may be used in the formulations and methods of thepresent invention, and all such agents are meant to be encompassed bythe term “dopamine agonists.” For example, such drugs include, but arenot limited to, carbidopa (Sinemnet®), dopamine agonists (Requip®,Rotigotine®, Mirapex®), COMT inhibitors (Entacapone®, Tocapone),rasagiline (Azilect®) (MAO inhibitors) and MAO-B inhibitors (Selegiline(Eldepryl®).

In other embodiments, the drug is opioid such as morphine, codeine,dihydrocodeine, hydrocodone, hydromorphone, nicomorphine, oxycodone,oxymorphone, fentanyl, alphamethylfentanyl, alfentanil, sufentanil,remifentanil, carfentanyl, ohmefentanyl, thebaine, oripavine,diacetylmorphine (heroin), phenylpiperidines such as pethidine(meperidine) and ketobemidone, allylprodine, prodine, propoxyphene,dextropropoxyphene, dextromoramide, bezitramide, piritramide, methadone,dipipanone, levomethadyl Acetate (LAAM), loperamide, diphenoxylate,dezocine, pentazocine, phenazocine, buprenorphine, dihydroetorphine,etorphine, butorphanol, nalbuphine, levorphanol, levomethorphan,lefetamine, meptazinol, tilidine, tramadol, tapentadol, mixturesthereof, and the like.

In yet other embodiments, the drug is tarpentadol (a centrally actingoral analgesic having two mechanisms of action combining mu-opioidreceptor agonism and norepinephrine reuptake inhibition).

In yet other embodiments, the drug is a selective norepinephrinereuptake inhibitor, such as Atomoxetine (Strattera®), Mazindol(Mazanor®, Sanorex®), Nisoxetine (LY-94939), Reboxetine (Edronax®,Vestra®), Viloxazine (Vivalan®), mixtures thereof, and the like.

In yet other embodiments, the drug is a benzodiazepine, such aslorazepam (Ativan®), diazepam (Valium®), clonazepam (Konopin®),chlordiazepoxide (Librium®), alprazolam (Xanax®), temazepam (Restoril®),mixtures thereof, and the like. In other embodiments, the drug is aneuroleptic or psychotropic such as chlorpromazine (Thorazine®),haloperidol (Haldol®), risperidone (Risperdal®), olanzapine (Zyprexa®)and quetiapine (Seroque®).

In other embodiments, the drug is an agent that treats depression and/oranxiety, for example, selective serotonin reuptake inhibitors (SSRIs)such as fluoxetine (Prozac), sertraline (Zoloft®), venlafaxine(Effexor®), citalopram (Celexa®), parocetine (Paxil), mixtures thereof,and the like (such as trazodone (Desyrel)), and/orserotonin-norepinephrine reuptake inhibitors (SNRI), such asDesvenlafaxine (Pristiq®), Duloxetine (Cymbalta®), Milnacipran (Ixel®,Savella®), Venlafaxine (Effexor®), mixtures thereof, and the like.

In yet other embodiments, the drug is a norepinephrine-dopamine reuptakeinhibitor (NDRI), such as Amineptine (Survector®), an aminoketoneantidepressant such as Bupropion (Wellbutrin®, Zyban®),Dexmethylphenidate (Focalin), Methylphenidate (Ritalin®, Concerta®),Nomifensine (Merital®), a phenylpiperazine antidepressant such asnefazodone (Serzone®), a piperazino-azepine antidepressant such asmirtazapine (Remeron®), mixtures thereof, and the like.

In yet other embodiments, the drug may be an NMDA receptor antagonist.Phencyclidine, ketamine, and dextromethorphan, are used as recreationaldrugs. At subanesthetic doses, however, these drugs have mild stimulanteffects, and these agents have shown promise for the treatment ofconditions that involve excitotoxicity, including traumatic braininjury, stroke, and neurodegenerative diseases such as Alzheimer's,Parkinson's, and Huntington's.

Additionally, the drug may be an agent that treatsneuropathic/neurogenic pain (pain that arises from nerve dysfunction andnot as a result of injury, e.g., trigeminal neuralgia), such ascarbamazepine, gabapentin, topiramate, zonisamide, phenytoin,desipramine, amitriptyline, imipramine, doxepin, protriptyline,pentoxifylline, and hydroxyzine.

In other embodiments, the drug treats insomnia, such as zolpidem(Ambien®).

In other embodiments, the drug treats fatigue. Such drugs includecentral nervous system stimulants such as pemoline (Cylert®) andModafinil (Provigil®).

In yet other embodiments, the drug treats vertigo, nausea and/ordizziness, such as meclizine (Antivert®), dimenhydrinate (dramamine),prochlorperazine (Compazine®), scopolamine (Transderrn) anddiphenhydramine (Benadryl®).

In yet other embodiments, the drug is a serotonin-norepinephrinereuptake inhibitor (SNRI), such as Desvenlafaxine (Pristiq®), Duloxetine(Cymbalta®), Milnacipran (IxelM, Savella®), Venlafaxine (Effexor®),mixtures thereof, and the like.

In yet other embodiments, the drug is a tricyclic antidepressant (TCA),such as Amitriptyline (Elavil®), Butriptyline (Evadene®, Evadyn®),Clomipramine (Anafranil®), Desipramine (Norpramin®, Pertofrane),Dosulepin (Prothiade), Doxepin (Adapin, Sinequan), Imipramine(Tofranil®), Lofepramine (Feprapax®, Gamanil®, Lomont®), Nortriptyline(Aventyl®, Nortrilen®, Pamelor®), Protriptyline (Vivacti®l),Trimipramine (Sumontil®), mixtures thereof, and the like.

In yet other embodiments, the drug is a tetracyclic antidepressant, suchas Amoxapine (Asendin®), Maprotiline (Ludiomil®), Mianserin (Tolvon(®),mixtures thereof, and the like.

In yet other embodiments, the drug is an atypical antipsychotic, such asZiprasidone (Geodon®, Zeldox®), Nefazodone (Serzonee®), and the like.

In yet other embodiments, the drug is an anti-convulsant oranti-epileptic drug such as arylsulfonimide analogues such asAcetazolimide (Diamox)®, tricyclic iminostilbene derivatives such ascarbamazepine (Tegreto®), benzodiazepines such as clonazepam(Klonopin®), clorazepate dipotassium (Tranxene®), lorazepam (Ativan®)and diazepam (Valium®), carboxylic acid derivatives such as valproicacid (Depakene®) and divalproex sodium (Depakote®), succinimidederivatives such as ethosuximide (Zarontin®), carbamate esters of2-phenyl-1,3-propanediol such as felbamate (Felbatol®), hydantoins suchas phenytoin (Dilantin®), phenytoin sodium (Dilantin®) and fosphenytoinsodium (Cerebyx®), structural analogues of GABA such as gabapentin(Neurontin®) and pregabalin (Lyrica®), phenyltriazines such aslamotrigine (Lamictal®), pyrrolidine derivatives such as levitiracetam(Keppra®), tricyclic iminostilbene derivatives such as oxcarbezepine(Trileptal), barbiturates such as Phenobarbital, desoxybarbiturates suchas primidone (Mysoline), nipecotic acid derivatives such as tiagabinehydrochloride (Gabitril®), sulfamated monosaccharides such as topiramate(Topamax®), oxazolidinedione derivatives such as trimethadione(Tridione®), and methanesulfonamides such as zonisamide (Zonigran®).Additional drugs such as Retigabine® (Valeant Pharmaceuticals),Lacosamide® (Schwarz Biosciences), and Perampanel® (Eisai) are indevelopment as anti-epileptics and neuromodulators for other associatedneurological, pain, and psychiatric conditions, and thus are furtherexamples of potentially useful drugs in the present invention.

In yet other embodiments, the drug is an analgesic/anti-inflammatoryagent such as acetaminophen; prednisone, solumedrol, and other steroids;naproxen, aspirin, voltaren, ketoprofen, ibuprofen, nabumetone, andother NSAID's. The NSAID may be COX-1, COX-2 or mixed COX-1/COX-2inhibitors. Examples of COX-2 inhibitors include oxicam, meloxicam, andthe more selective celecoxib, rofecoxib, valdecoxib, parecoxib andetoricoxib. Further examples of corticosteroids includemethylprednisolone, prednisolone, dexamethasone, andadreno-corticotrophic hormone (ACTH), corticotropin.

Additionally, the drug may be an agent that treatsneuropathic/neurogenic pain (pain that arises from nerve dysfunction andnot as a result of injury, e.g., trigeminal neuralgia), such ascarbamazepine, gabapentin, topiramate, zonisamide, phenytoin,desipramine, amitriptyline, imipramine, doxepin, protriptyline,pentoxifylline, and hydroxyzine, mixtures thereof, and the like.

In other embodiments the drug is partial agonist at the a42 nicotinicacetylcholine receptors, used for smoking cessation. The characteristicsof varenicline (Chantix®), having a molecular weight (MW) of 261 andhigh water solubility, make it ideal for topical delivery. The usualadult dose of varenicline for smoking cessation is: Days 1-3: 0.5 mgorally once a day; Days 4-7: 0.5 mg orally twice a day Days 8—end oftreatment: 1 mg orally twice a day, for one or two twelve week cycles oftreatment. Another agent in this class is cytosine (Tabex®), which is aplant alkaloid and is marketed for smoking cessation in Europe.

In other embodiments, the drug is 4-aminopyridine (4-AP; also known asFampridine®) or a pharmaceutically acceptable derivative thereof. Thisdrug has been shown to have the ability to improve the communicationbetween damaged nerves, which may result in increased neurologicalfunction in the treatment of conditions such as multiple sclerosis (MS).An example of another such drug is 3,4 diaminopyridine.

In yet other embodiments, the drug is an appetite suppressant, such asSibutramine (Meridia®, Reductil®), which is a centrally actingserotonin-norepinephrine reuptake inhibitor that is structurally relatedto amphetamines but having a distinct mechanism of action. Otherpotentially useful drugs for anti-obesity include Rimonabant(Acomplia®), substances related to amphetamine, such as phentermineand/or fenfluramine and/or dexfenfluramine, (the combination popularlyreferred to phen-fen) may also be useful in the treatments of thepresent invention. It is believed that the present method of treatmentwould avoid the potential heart value damage found with thesecombinations when administered orally.

In other embodiments, the drug is useful for the treatment ofDementia/Alzheimer's disease, such as Aricept/donepezil,Exelon®/rivastigmine, Reminyl®/Razadyne®/galantaminc, andNamenda®/memantine, their naturally occurring counterparts, and mixturesthereof.

In other embodiments, the drug is useful for the treatment of ADD, ADHD,and similar conditions, and the drug is, for example, one or moreamphetamine derivatives or isomers thereof, such as lisdexamfetamine(Vyvance®), Adderall® (75% d-amphetamine and 25% l-amphetamine,methylphenidate (Ritalin®, Concerta®), dextroamphetamine,dexmethylphenidate hydrochloride (Focalin®), Ritalin®), atomoxetine(Strattera®), mixtures thereof and the like.

It has been observed and reported that patients given apomorphineinjections regularly developed penile erections. Some of these patientshad problems of impotence with erectile dysfunction. These patientsreported improvement in sexual function with apomorphine injections.Animal studies suggest central dopamine D2 receptor stimulation may bemediating this effect. It is also known that the male sexual response isrelated to the autonomic nervous system: primarily the parasympatheticcomponent for erection and, the sympathetic for ejaculation. Thissuggests the possible role of apomophine delivered as TRNA BONATHtherapy for the treatment of sexual dysfunction in Parkinson's diseaseas well as from other conditions. Thus, the present invention alsoencompasses the use of apomorphine and other dopamine agonists (e.g., asset forth above), as well as sildenafil (Viagra®), vardenafil(Levitra®), tadalafil (Cialis®), alprostadil (Prostin®), and mixtures ofany of the foregoing.

Formulations

All currently approved therapies for the conditions described abovereach the central nervous system through the systemic circulation.Cerebral blood flow to brainstem structures is through the posteriorcirculation, via the vertebral and basilar arteries and their branches.In view of the undesirable side-effects associated with this form ofdrug delivery to the brain, it makes sense that targeted regionaldelivery to the brainstem is sought. Topical delivery of currently useddrugs compounded in an appropriate “dermal penetration enhancer” andapplied in cream/gel form or as a sustained-release patch at theposterior cervical region (back of the neck) at the hairline is such amethod. Lipoderm® is an example of an effective commercially availablecompounding medium. However, one skilled in the art will recognize thattopical carriers meeting the specific chemical requirements of anindividual drug can be formulated for maximum efficiency in topicaldelivery.

The formulations of the present invention are prepared such that thedrug(s) may be delivered acutely as single dose applications ascream/gel/ointment or as a sustained release topical patch, depending onthe condition treated and associated symptom complex in the individualpatient. The critical point, again, is in the location of theapplication: at the back of neck at the hair-line for access toposterior cervical afferents with free nerve endings under the surfaceof the skin. Through feedback connections with vagal and trigeminalafferent systems, this results in ultimate effect on brainstemstructures.

By virtue of the method of treatment described herein, the diseasestate/condition to be treated may be treated much faster and moreeffectively than such prior art modes of administration.

In certain embodiments of the present invention, the method of treatinga human patient comprises applying a topical formulation which comprisesa drug suitable for topical administration, which is useful for thetreatment of a disease state or condition treatable via the topicalbrainstem afferent stimulation (de-afferentation) drug therapy describedherein.

The methods of the present invention may also, if desired, involvepre-treatment of the skin with an enhancer to increase the permeabilityof the skin to the applied drug. The methods of the present inventionmay include pre-treatment or “prepping” of the skin area with asubstance that opens up the skin pores. Additionally, the methods of thepresent invention may include, if desired, pre-treatment or “prepping”of the skin with an alcohol swab or the like to rid the area of dirt,make-up, oil, and the like, prior to application of the drug.

In certain embodiments, the topical formulation of the present inventioncomprises a drug in an amount which is therapeutically effective whenadministered topically at the at the back of neck at the hair-line foraccess to posterior cervical afferents with free nerve endings under thesurface of the skin, but which provides a plasma concentration which issubtherapeutic if orally administered.

In certain embodiments, by applying the formulation of the presentinvention comprising a dose of drug at the back of neck at the hair-linefor access to posterior cervical afferents with free nerve endings underthe surface of the skin, it may be possible for the use of lower dosesof drug or faster relief of the headache than if applied to the trunk orlimbs of a human patient, and the lower plasma levels of drug whichresult from lower doses may thereby reduce unwanted side effects of thedrug.

The topical formulations of the present invention (e.g., ointment, gel,cream, or the like), must be suitable for topical administration of adrug, i.e., must contain pharmaceutically acceptable excipientscompatible with application to the skin tissue, and may optionallycontain a sufficient amount of an enhancer composition as describedhereinafter.

In certain embodiments, in addition to the drug (e.g., dopamineagonist), the topical formulations and/or transdermal therapeuticsystems of the present invention may include at least one adjuvant suchas a penetration enhancer, anti-oxidant, stabilizer, carrier, orvehicle. Additionally or alternatively, the present invention mayinclude the application of electric current (iontophoresis) forenhancing permeation of the dopamine agonist.

In certain embodiments, the topical formulations comprising a drug in anointment, gel, cream or the like, will typically contain on the order ofabout 0.001 to about 80% by weight, preferably 0.01 wt. % to 50 wt. %drug, and about 0 wt. % to about 50.0 wt. %, preferably from about 1 wt.% to about 30 wt. % of a permeation enhancer composition, with theremainder of the composition comprising a carrier or vehicle. In certainpreferred embodiments, the drug is included in a cream or gel orointment in a concentration of, e.g., 1 mg drug/mi of carrier (e.g.,Lipoderm). However, it is to be understood that one skilled in the artcan increase the amount of carrier or change the carrier and maintain orimprove efficacy of the topical formulation for TRNA therapy.

In certain embodiments, the topical formulations comprising a dopamineagonist in an ointment, gel, cream or the like, will typically containon the order of about 0.001 to about 80% by weight, preferably 0.01 wt.% to 50 wt. % dopamine agonist, and about 0 wt. % to about 50.0 wt. %,preferably from about 1 wt. % to about 30 wt. % of a permeation enhancercomposition, with the remainder of the composition comprising a carrieror vehicle. In certain preferred embodiments, the dopamine agonist isapomorphine and is included in a cream or gel or ointment in aconcentration of, e.g., 1 mg drug/mi of carrier (e.g., Lipoderm).However, it is to be understood that one skilled in the art can increasethe amount of carrier or change the carrier and maintain or improveefficacy of the topical formulation for TRNA therapy. In certainpreferred embodiments, the drug is applied as a unit dose at the BONATHin immediate release form (e.g., cream, ointment or gel) for acutetreatment with a dopamine agonist as would be beneficial to a personsuffering from, e.g., Parkinson's disease or impotence/male erectiledysfunction. In such instances, it is preferred that the concentrationof dopamine agonist included in the unit dose is from about 0.25 mg toabout 4 mg, based on apomorphine, or an therapeutically equivalentamount of another dopamine agonist as described herein.

Suitable permeation enhancers may also be included in the formulations.Such enhancers include, but are not limited to, dimethylsulfoxide(DMSO), N,N-dimethylacetamide (DMA), decylmethylsulfoxide (C10 MSO),polyethylene glycol monolaurate (PEGML), propylene glycol (PG), PGML,glycerol monolaurate (GML), lecithin, the 1-substitutedazacycloheptan-2-ones, particularly 1-n-dodecylcyclazacycloheptan-2-one(available under the trademark Azone® from Whitby Research Incorporated,Richmond, Va.), alcohols, and the like. The permeation enhancer may alsobe a vegetable oil as described in U.S. Pat. No. 5,229,130 to Sharma.Such oils include, for example, safflower oil, cotton seed oil and cornoil.

Additional enhancers for use in conjunction with the present inventionare lipophilic compounds having the formula [RCOO]n R′, wherein n is 1or 2 and R is C1-C16 alkyl optionally substituted with 1 or 2 hydroxylgroups, and R′ is hydrogen or C1-C16 alkyl optionally substituted with 1or 2 hydroxyl groups. Within this group, a first subset of compounds arerpresented by the formula [CH3 (CH 2)m COO]n R′ in which m is an integerin the range of8 to 16, n is 1 or 2, and R′ is a lower alkyl (C1-C3)residue that is either unsubstituted or substituted with one or twohydroxyl groups. Preferred enhancers within this group include an esterwhich is a lower alkyl (C1-C3) laurate (i.e., m is 10 and n is 1) suchas “PGML”. It will be appreciated by those skilled in the art that thecommercially available material sold as “PGML” is typically although notnecessarily a mixture of propylene glycol monolaurate itself, propyleneglycol dilaurate, and either propylcne glycol, methyl laurate, or both.Thus, the terms “PGML” or “propylene glycol monolaurate” as used hereinare intended to encompass both the pure compound as well as the mixturethat is typically obtained commercially. Also within this group is asecond subset of compounds, namely, esters of fatty alcohols representedby the formula CH3 (CH2)m-O—CO—CHR1 R2, in which R1 and R2 areindependently hydrogen, hydroxyl, or lower alkyl (C1-C3), and m is asabove. Particularly preferred enhancers within this group are lauryllactate and myristyl lactate. In addition, a third subset of compoundswithin this group are analogous fatty acids, i.e., acids having thestructural formula CH3 (CH2)m COOH where m is as above. A particularlypreferred acid is lauric acid.

Other enhancer compositions are wherein a lipophilic compound as justdescribed, particularly PGML is combined with a hydrophilic compound,such as a C2-C6 alkanediol. One preferred hydrophilic enhancer withinthis group is 1,3-butanediol. Such enhancer compositions are describedin detail in PCT Publication No. WO 95/05137, published Feb. 23, 1995,herein incorporated by reference. Another hydrophilic enhancer that maybe included in these compositions is an ether selected from the groupconsisting of diethylene glycol monoethyl ether (Transcutol) anddiethylene glycol monomethyl ether. Such enhancer compositions aredescribed in detail in U.S. Pat. Nos. 5,053,227 and 5,059,426 to Chianget al., the disclosures of which are herein incorporated by reference.

Other enhancer compositions may include mixture or combinations of anyof the aforementioned enhancers, and the like.

In certain embodiments the topical formulation may include at least onewater-insoluble, pharmacologically approved, alkyl cellulose orhydroxyalkyl cellulose, and the like. Alkyl cellulose or hydroxyalkylcellulose polymers for use in this invention include ethyl cellulose,propyl cellulose, butyl cellulose, cellulose acetate, hydroxypropylcellulose; hydroxybutyl cellulose, and ethylhydroxyethyl cellulose,alone or in combination. In addition, a plasticizer or a cross linkingagent may be used to modify the polymer's characteristics. For example,esters such as dibutyl or diethyl phthalate, amides such asdiethyldiphenyl urea, vegetable oils, fatty acids and alcohols such asacid oleic and myristyl may be used in combination with the cellulosederivative.

In certain embodiments, the topical formulation may further includehydrocarbons such as liquid paraffin, vaseline, solid paraffin,microcrystalline wax, etc.; higher aliphatic alcohols such as cetylalcohol, hexadecyl, alcohol, stearyl alcohol, oleyl alcohol, etc.;esters of higher fatty acids with higher alcohols such as beeswax, etc.;esters of higher fatty acids with lower alcohols such as isopropylmyristate, isopropyl palmitate, etc.; vegetable oils, modified vegetableoils, hydrous lanolin and its derivative, squalene, squalane; higherfatty acids such as palmitic acid, stearic acid, etc. and the like.

In certain embodiments, the topical formulation may further includeemulsifiers and dispersing agents which include, for example, anionic,cationic and nonionic surfactants. Nonionic surfactants are preferredbecause of their low levels of irritation to skin. Typical of nonionicsurfactants are fatty acid monoglycerides such as glyceryl monostearate,etc.; sorbitan fatty acid esters such as sorbitan monolaurate, etc.;sucrose fatty acid esters; polyoxyethylene fatty acid esters such aspolyoxyethylene stearate, etc.; and polyoxyethylene higher alcoholethers such as polyoxyethylene cetyl ether, polyoxyethylene oleyl ether,etc.

In certain preferred embodiments, the topical TRNA formulation isaqueous-based.

In certain embodiments of the present invention, the topical formulationmay include a gelling agent such as methylcellulose, ethylcellulose,hydroxyethylcellulose, hydroxypropyl-cellulose,hydroxyprpylmethylcellulose, carboxymethylcellulose, carbomer, and thelike. Examples of pharmaceutical compositions which rely upon an aqueousgel composition as a vehicle for the application of a drug are U.S. Pat.Nos. 4,883,660; 4,767,619; 4,511,563; 4,861,760; and 5,318,780, thedisclosures of which are herein incorporated by reference.

The topical formulation may further include one or more preservatives,stabilizers, or anti-oxidants.

Examples of preservatives that may be used in a formulation according tothe present invention include, but are not limited to, bacteriostaticcompounds and other preservatives suitable for topical administrationincluding various alcohols, sorbic acid and salts and derivativesthereof, ethylenediamine, monothioglycerol, and thimerosal.

Examples of stabilizers that may be present in a formulation accordingto the present invention include pH buffers suitable for topicaladministration, complexing agents, chelating agents and the like.

Examples of anti-oxidants that may be used in a formulation according tothe present invention include ascorbic acid and its derivatives, e.g.,ascorbyl palmitate, as well as butylated hydroxyanisole, butylatedhydroxytoluene, sodium bisulfite, sodium metabisulfite, and others.

Other adjuvants that may be included in the drug formulation includecarriers, tackifiers, pigments, dyes, and other additives that do notadversely affect the mechanical or adhesive properties of theformulation.

“Carriers” or “vehicles” as used herein refer to carrier materialssuitable for transdermal drug administration, and include any suchmaterials known in the art, e.g., any liquid, gel, emulsion, solvent,liquid diluent, solubilizer, or the like, which is nontoxic and whichdoes not interact with other components of the composition in adeleterious manner. The term “carrier” or “vehicle” as used herein mayalso refer to stabilizers, crystallization inhibitors, dispersing agentsor other types of additives useful for facilitating transdermal drugdelivery. It will be appreciated that compounds classified as “vehicles”or “carriers” maysometimes act as permeation enhancers, and vice versa,and, accordingly, these two classes of chemical compounds orcompositions may sometimes overlap.

Carrier materials suitable for use in the instant compositions includethose well-known for use in the cosmetic and medical arts as bases forointments, lotions, salves, aerosols, suppositories and the like.Suitable carniers include, for example, water, liquid alcohols, liquidglycols, liquid polyalkylene glycols, liquid esters, liquid amides,liquid protein hydrolysates, liquid alkylated protein hydrolysates,liquid lanolin and lanolin derivatives, and like materials commonlyemployed in cosmetic and medicinal compositions. Other suitable carriersherein include for example alcohols, including both monohydric andpolyhydric alcohols, e.g., ethanol, isopropanol, glycerol, sorbitol,2-methoxyethanol, diethyleneglycol, ethylene glycol, hexyleneglycol,mannitol, and propylene glycol; ethers such as diethyl or dipropylether, polyethylene glycols and methoxypolyoxyethylenes (carbowaxeshaving molecular weight ranging from 200 to 20,000); polyoxyethyleneglycerols, polyoxyethylene sorbitols, stearoyl diacetin, and the like.

In certain preferred embodiments of the present invention where it isdesired that the drug (.e.g., dopamine agonist) is administeredchronically, the formulations of the present invention may be formulatedas a transdermal delivery system (also referred to herein as atransdermal therapeutic system) such as a transdermal patch, atransdermal plaster, a transdermal disc, iontophoretic transdennaldevice, or the like. Such formulations are recognized by those skilledin the art as providing a release of drug and absorption into the skinof the patient in a sustained manner over an extended period of time(e.g., 1-7 days). In such embodiments of the present invention, thetransdermal delivery system comprises, e.g., a dopamine agonistcontained in a reservoir or a matrix, and an adhesive which allows thetransdennal patch to adhere to the skin, allowing the passage of theactive agent from the transdermal patch through the skin of the patient.In preferred embodiments, the transdermal patch is applied topically atthe back of the neck at the hairline (“BONATH”) so as to achieve topicalregional neuro-affective therapy (“TRNA THERAPY”) as described herein.In embodiments in which the drug is contained in a transdermal patch, itis contemplated that the drug will be absorbed more slowly and thetransdermal patch will provide a sustained release and prolongedtherapeutic effect, as compared, e.g., to a cream or ointment intendedto provide an immediate release of the drug and rapid onset of the TRNAtherapy.

In certain embodiments, the transdermal delivery devices, as well asother trandermal delivery systems in accordance with the invention canbe made in the form of an article such as a tape, a patch, a sheet, adressing or any other form known to those skilled in the art. Generallythe device will be in the form of a patch of a size suitable to delivera unit dose of serotonin agonist through the skin. The drug may beintroduced into a transdermal therapeutic system in different forms(solid, in solution, in dispersion); it may also be microencapsulated.

In certain embodiments the present invention provides a transdermaltherapeutic system comprising a drug (e.g., serotonin agonist) in anamount that would provide sub-therapeutic plasma levels if administeredorally, but is therapeutically effective when administered viatransdermal delivery at the headache region.

A transdermal delivery system for use in accordance with the presentinvention can also be constructed with an enhancer composition and otheringredients described hereinabove with respect to the topicalformulation. Preferably, the transdermal delivery system is formulatedfor the prolonged delivery of a drug (e.g., dopamine agonist) as wouldbe beneficial to a person suffering from, e.g., Parkinson's disease orimpotence/male erectile dysfunction. The targeted skin flux for deliveryof a particular drug can be achieved by adjusting vehicle compositionand vehicle loading, as well as by adjusting the surface area throughwhich the compositions are administered to skin.

In certain preferred embodiments, the transdermal delivery system (e.g.,patch) is formulated to deliver from about 4 mg to about 50 mg of thedopamine agonist per each 24 hours through the skin of the patient,based on apomorphine, or a therapeutically equivalent amount of asuitable alternative dopamine agonist as described herein. Inembodiments in which the transdermal delivery system is intended to beapplied to the skin at the BONATH for multiple days, the transdermaldelivery system (e.g., patch) is formulated to provide a flux rate overthe useful life of the system such that a similar amount (e.g., meandose) is delivered on a daily basis until the system is removed andreplaced with a fresh system.

The transdermal delivery system used in the present invention may beprepared, for example, in accordance with U.S. Pat. Nos. 5,069,909;4,806,341; 5,026,556; 4,588,580; 5,016,652; 3,598,122; 4,144,317;4,201,211; 4,262,003; and 4,379,454; all of which are incorporatedherein by reference.

Additionally, the transdermal delivery system used in the presentinvention may be in accordance with U.S. Pat. No. 6,689,379, herebyincorporated by reference, which system is a matrix or reservoir systemwhich comprises: at least one pharmaceutical active agent selected fromthe group consisting of basic pharmaceutical active agents and neutralpharmaceutical active agents (such as rivastigmine); and apressure-sensitive adhesive comprising a polyacrylate polymer, whereinsaid polyacrylate polymer has a polyacrylate backbone containing monomerunits selected from the group consisting of acrylic acid, methacrylicacid and ester derivatives of acrylic or methacrylic acid, and saidmonomer units comprise at least 50% (w/w) relative to a mean polymermass of said polyacrylate polymer, a total amount of monomers selectedfrom the group consisting of non-esterified acrylic acid andnon-esterified methacrylic acid is 0.5 to 10.0% (w/w) relative to themean polymer mass of said polyacrylate polymer, and the carboxyl groupsof said non-esterified acrylic and methacrylic acid monomers are presentstoichiometrically at 5 to 100% in the form of alkali salts oralkaline-earth salts, said salts being reaction products of aneutralization reaction of an alcoholic solution of an alkalinehydroxide or an alkaline-earth hydroxide with said acrylate polymer(s),or of a neutralization reaction of an alkali alcoholate or analkaline-earth alcoholate with said acrylate polymer(s).

In certain embodiments, the dosage form can be a transdermal patchcomprising a laminated composite for administering the drug (e.g.,dopamine agonist) to an individual transdermally comprising: (a) apolymer backing layer that is substantially impermeable to the dopamineagonist; and (b) a reservoir layer comprising a water-base acrylatepressure-sensitive adhesive, 1 to 12% by weight serotonin agonist and 2to 25% by weight of a permeation enhancer comprising propylene glycolmonolaurate in combination with capric acid or oleic acid, wherein theskin contact area of the composite is 10 to 100 cm2.

The dosage form can be a transdermal patch comprising (a) a polarsolvent material selected from the group consisting of C3-C4 diols,C3-C6 triols, and mixtures thereof; and (b) a polar lipid materialselected from the group consisting of fatty alcohol esters, fatty acidesters, and mixtures thereof; wherein said polar solvent material andsaid polar lipid material are present in a weight ratio of solventmaterial:lipid material of from about 60-40 to about 99:1.

In certain embodiments, the dosage form also comprises a transdermalplaster comprising: (1) a film layer which comprises a polyester filmof0.5 to 4.9 microns thickness, 8 to 85 g/mm strength, respectively inthe two directions intersecting substantially at right angles, 30 to150% elongation, in the two directions intersecting substantially atright angles and an elongation ratio of A to B of 1.0 to 5.0, wherein Aand B represent data in two directions intersecting at right angles, andA is greater than B, and wherein said polyester film comprises 0.01 to1.0% by weight, based on the total weight of said polyester film, ofsolid fine particles in which (a) the average particle size is 0.001 to3.0 microns, and (b) the average particle size is substantially not morethan 1.5 times the thickness of said polyester film; and (2) an adhesivelayer (a) which is composed of an adhesive containing said serotoninagonist and further wherein said adhesive layer (a) is laminated on saidfilm layer over the surface in a 2 to 60 microns thickness.

In certain embodiments, the dosage form can be a transdermal disccomprising: (a) a backing layer which is substantially impervious to thedopamine agonist; and (b) a polymer matrix disc layer which is adheredto said backing layer and which has microdispersed therein saidserotonin agonist, said polymer being bioacceptable and permitting saidserotonin agonist to be transmitted for transdermal absorption, thedopamine agonist being stable in said polymer matrix.

In certain embodiments, the topical formulation or transdermaltherapeutic system may further comprise another active ingredient incombination with the first drug (e.g., dopamine agonist), e.g.,analgesics, antimimetics, psychopharmacologic agents, or sedatives.

The present invention is contemplated to encompass all transdermalformulations, e.g., the technologies described above, with the inclusionof a drug (e.g., dopamine agonist(s)), such that the administration of adrug useful for treatment of disease state or condition in humans viatopical brainstem afferent stimulation (de-afferentation) therapy viatopical administration. Therefore, modifications of the invention via,e.g., the choice and/or amount of drug are considered to be obviousvariations of this disclosure and within the scope of the appendedclaims.

The present invention also contemplates the administration of the drug(e.g., dopamine agonist) directly below the skin to affect directbrainstem afferent stimulation to the free nerve endings under theepidermis. Such administration may be effected as an injection (e.g.,subcutaneous injection) or implantation of the drug in immediate releaseor sustained release form. It will be appreciated by those skilled inthe art that providing the drug in Sustained release form andadministering it in a suitable form below the skin may provide benefits,including less frequent administration (e.g., in chronic therapy).

In certain embodiments of the invention, the drug (e.g., dopamineagonist) can be formulated for controlled or sustained delivery at theBONATH via incorporation into a biocompatible and implantable polymerwhich can be in the form of microparticles or an implantable insert, ora liquid that forms a gel or colloid or a semi-solid after injection(thereby encapsulating the drug and allowing it to be released in aprolonged and controlled manner at the desired site). For chronicconditions (e.g., Parkinson's) or desired prolonged effect, it iscontemplated that a drug depot or reservoir may be created under theskin at the BONATH, which then provides a sustained release of the drugin proximity to the desired nerve endings and which may be replenishedor replaced at the end of the dosing interval. It is contemplated thatsuch administrations of the drug (e.g., dopamine agonist) may provide aprolonged therapeutic effect for at least about 3 days, preferably atleast about 7 days, or longer. Such formulations may be administered incertain embodiments as, for example, a subcutaneous depot.

Implants are placed subcutaneously by making an incision in the skin andforcing the implants between the skin and the muscle. At the end oftheir use, if not dissolved, these implants are surgically removed. U.S.Pat. No. 4,244,949, hereby incorporated by reference, describes animplant which has an outer matrix of an inert plastic such aspolytetrafluoroethylene resin. Examples of this type of implantabletherapeutic system are Progestasert IUD and Ocusert system. It iscontemplated that such systems can be appropriately modified by oneskilled in the art for use in conjunction with the present invention. Acommercially available product, Norplant®, which is an implant having acore containing levonorgestrel as the active substance, and where thecore it surrounded by a membrane of a silicone elastomer ofpoly(dimethylsiloxane) (PDMS). Another preparation of this kind isJadelle®, in which the core is a poly(dimethylsiloxane) based matrixwith levonorgestrel dispersed therein. The membrane is an elastomer madefrom PDMS and silica filler, which, besides giving necessary strengthproperties to the membrane, also retards the permeation of the activeagent through the membrane. U.S. Pat. No. 3,854,480, hereby incorporatedby reference, describes a drug delivery device, e.g. an implant, forreleasing a drug at a controlled rate for a prolonged period of time.The device has a core of a matrix in which the drug is dispersed. Thecore is surrounded by a membrane that is insoluble in body fluids. Thecore matrix as well as the membrane are permeable to the drug bydiffusion. The materials of the core and the membrane are chosen so thatthe drug diffuses through the membrane at a lesser rate than through thecore matrix. Thus, the membrane controls the release rate of the drug.As a suitable polymer for the core matrix is mentionedpoly(dimethylsiloxane) (PDMS), and as suitable polymers for the membraneare mentioned polyethylene and a copolymer of ethylene and vinyl acetate(EVA). It is contemplated that the above systems may be adapted by oneskilled in the art to deliver the drug (e.g., dopamine agonists) inaccordance with the present invention.

One device which may be adapted by one skilled in the art for use in thepresent invention is described in U.S. Pat. No. 5,968,542 (Tipton),hereby incorporated by reference, which describes a high viscosityliquid controlled delivery system as a medical or surgical device isprovided that includes: (i) a non-polymeric, non-water soluble liquidcarrier material (HVLCM) of viscosity of at least 5,000 cP at 37.degree.C. that does not crystallize neat under ambient or physiologicalconditions; and, optionally, (ii) a substance to be delivered.

The pharmaceutical compositions suitable for injectable use inaccordance with this invention include sterile aqueous solutions ordispersions and sterile powders or lyopholysates for the extemporaneouspreparation of sterile injectable solutions or dispersions. The dosageforms must be sterile and it must be stable under the conditions ofmanufacture and storage. The carrier for injectable formulations istypically water but can also include ethanol, a polyol (for example,glycerol, propylene glycol and liquid polyethylene glycol), mixturesthereof, and vegetable oil.

Injectable formulations used in the present invention can also beformulated as injectable prolonged release formulations in which theactive compound is combined with one or more natural or syntheticbiodegradable or biodispersible polymers such as carbohydrates,including starches, gums and etherified or esterified cellulosicderivatives, polyethers, polyesters, polyvinyl alcohols, gelatins, oralginates. Such dosage formulations can be prepared for example in theform of microsphere suspensions, gels, or shaped polymer matrix implantsthat are well-known in the art for their function as “depot-type” drugdelivery systems that provide prolonged release of the biologicallyactive components. Such compositions can be prepared usingart-recognized formulation techniques and designed for any of a widevariety of drug release profiles.

One example of a useful formulation which may be used in the methods ofthe present invention for providing a prolonged duration of action isdescribed in U.S. Pat. No. 7,332,503 (Wikstrom, et al.), herebyincorporated by reference. Therein, apomorphine derivatives and thephysiologically acceptable salts thereof as well as formulations thereofare described which provide a prolonged duration of action. Theapomorphine pro-drugs can be suspended (as a neat oil or as crystals, ordissolved in a suitable and pharmaceutically acceptable solvent (e.g.water, ethanol, DMSO, i-PrOH or benzylbenzoate)) in a pharmaceuticallyacceptable depot oil (e.g. viscoleo, sesame oil or olive oil) andinjected subcutaneously or intramuscularly with a syringe or a “peninjector”. Alternatively, these drugs may, in a suitable composition andwith a suitable vehicle (penetration enhancer), be applied to a patchfor transdermal administration. The composition could include also alocal anesthetic (e.g. lidocaine) to avoid injection pain, in particularat intramuscular injections. In one embodiment, the composition is inthe form of a patch or an ointment for transdermal administration. Thepatch or ointment preferably also comprises stabilizers, solubilizersand permeation activators to facilitate the passage of the activeprinciple through the skin. In another preferred embodiment, thecomposition is in the form of a depot preparation for subcutaneous orintramuscular administration comprising an apomorphine derivative or thephysiologically acceptable salt thereof dissolved or suspended in anoil. In certain embodiments, in addition to the apomorphine derivative,the formulation further contains a local anesthetic. The formulationsdescribed in the '503 patent can be modified as understood by oneskilled in the art to contain other active drugs as described herein foruse at the BONATH.

An injectable depot formulation is a dosage form, which is generallyintended to have a therapeutic activity for 2 to 4 weeks afteradministration (e.g. neuroleptics like Fluphenazine decanoate in sesameoil). In order to maintain effective drug plasma levels the dosage formshould release the drug at a more or less constant rate during thedesired dosing interval. The difference between such prior art depotsand depots used in the present invention is that the in accordance withthe present invention, the drug is not needed to be absorbed into thesystemic circulation.

A suitable form of depot preparation is the subcutaneous orintramuscular administration of an oil solution and/or oil suspension ofa lipophilic drug. This gives a slow transport over the oil-biofluidinterface and a slow dissolution in the biophase. Thus, when the drug isdissolved in a polar solvent (e.g. oils), which is non-miscible with theaqueous biological fluids, the drug has to be transported over theoi/water interface. When the oil/water partition coefficient is high,the transport will be slow. For very lipophilic drugs, the release fromthe oil phase may last for up to several weeks. The use of depotpreparations such as those described herein may be used to deliver thedrugs described herein at the BONATH.

The maximum volume of an oil solution/suspension to be injectedintramuscularly or subcutaneously is 2-4 mL. This is feasible for thepreparations of the aporphine derivatives of the present invention. Theaccumulated daily dose used in apomorphine s.c. therapy in Parkinson'sdisease is, e.g., 4-10 times about 1-4 mg (4-40 mg/day). For example, 2mg Apomorphine HCl (or equivalent molar amount of another dopamineagonist(s), as the base or as a suitable salt or ion-pair) may bedissolved in 1 mL of an oil (sesame oil, Viscoleo or another approvedoil) and the mixture gently heated (max 50° C.) shaken in a test tubeshaker and ultrasonicated for a short time (minutes) until the mixturebecomes a homogeneous solution or suspension. If necessary, the dopamineagonist may first be dissolved in 50-300 .mu.L DMSO, water, t-BuOH, PEG,benzylbenzoate, or another suitable and approved solvent or mixturesthereof, before adding the oil to a total volume of 1 mL.

Another example of a polymeric drug delivery system which may be adaptedfor use in the present invention by one skilled in the art is describedin U.S. Pat. No. 5,601,835 (Sabel, et al.), hereby incorporated byreference, which describes a polymeric drug delivery system for deliveryof any substance to the central nervous system. The delivery system ispreferably implanted in the central nervous system for delivery of thedrug directly to the central nervous system. These implantable devicescan be used, for example, to achieve continuous delivery of dopamine,which cannot pass the blood brain barrier, directly into the brain foran extended time period. The implantable devices display controlled,“zero-order” release kinetics, a life time of a minimum of several weeksor months even when the devices contain water soluble, low molecularweight compounds, biocompatibility, and relative non-invasiveness. Thepolymeric devices are said to be applicable in the treatment of avariety of central nervous system disorders including Parkinson'sdisease, Alzheimer's dementia, Huntington's disease, epilepsy, trauma,stroke, depression and other types of neurological and psychiatricillnesses, and one skilled in the art can adapt that drug deliverysystem for delivering the drugs contemplated herein at the BONATH.

Yet another example of a system that may be adapted for use in thepresent invention is described in U.S. Pat. No. 5,601,835 (Sabel, etal.), hereby incorporated by reference, wherein a compound such asdopamine is encapsulated within a polymer to form a polymeric device,the device formed of a biocompatible polymer that is plasticallydeformable selected from the group consisting of ethylene vinyl acetate,polyurethanes, polystyrenes, polyamide, polyacrylamide, and combinationsthereof having a non-porous polymer coating thereon with one or moreopenings, with limited water sorptivity and slight permeability to thepassage of small, aqueous-soluble molecules, wherein said compound islinearly released (e.g., zero order release) from said polymeric deviceover a sustained period of time of at least 65 days at a predeterminedlevel and rate when implanted in a patient at a specific site within thecentral nervous system where the compound is released directly into thecentral nervous system and the device remains essentially intactthroughout the release period. The delivery device is a two-phase systemwhich is manufactured using standard techniques such as blending, mixingor the equivalent thereof, following selection of the biologicallyactive material to be delivered and an appropriate polymer for formationof the matrix. The general method of solvent casting as disclosed bySiegel and Langer, “Controlled release of polypeptides and othermacromolecules”, Pharmaceutical Research 1, 2-10 (1984), is modified sothat drug is dispersed within the devices to create channels and poresto the surface for release of the drug at the desired rate. Whereappropriate, a coating impermeable to the drug is placed over a portionof the drug containing polymer matrix to further regulate the rate ofrelease. One skilled in the art can adapt that drug delivery system fordelivering the drugs contemplated herein at the BONATH.

Yet another formulation which may used to deliver the drug (e.g.,dopamine agonists) as set forth in the present invention at the BONATHis described in U.S. Pat. No. 7,314,636 (Caseres, et al.), herebyincorporated by reference, which describes injectable implantscomprising glycolic acid and bio-compatible/bio-absorbablc polymericparticles containing a polymer of lactic acid. The particles are smallenough to be injected through a needle but large enough to avoidengulfment by macrophages. The injectables of this invention may be in apre-activated solid form or an activated form (e.g., injectablesuspension or emulsion).

It is further contemplated that the system described in U.S. Pat. No.6,586,006 (Roser, et al.), hereby incorporated by reference, can beadapted by one skilled in the art for use in the present invention fordelivery of drugs at the BONATH. Therein are described delivery systemssuitable for delivery of bioactive materials to subcutaneous andintradermal, intramuscular, intravenous tissue, the delivery systembeing sized and shaped for penetrating the epidermis. The deliverysystems comprises a vitreous vehicle loaded with the guest substance andcapable of releasing the guest substance in situ at various controlledrates. Subdermal implantable therapeutic systems have also beenformulated for slow release of certain pharmaceutical agents forextended periods of time such as months or years. A well-known exampleis Norplant® for delivery of steroid hormones.

In membrane permeation-type controlled drug delivery, the drug isencapsulated within a compartment that is enclosed by a rate-limitingpolymeric membrane. The drug reservoir may contain either drug particlesor a dispersion (or solution) of solid drug in a liquid or a matrix typedispersing medium. The polymeric membrane may be fabricated from ahomogeneous or a heterogeneous nonporous polymeric material or amicroporous or semipermeable membrane. The encapsulation of the drugreservoir inside the polymeric membrane may be accomplished by molding,encapsulation, microencapsulation, or other techniques. The implantsrelease drugs by dissolution of the drug in the inner core and slowdiffusion across the outer matrix. The drug release from this type ofimplantable therapeutic system should be relatively constant and islargely dependent on the dissolution rate of the drug in the polymericmembrane or the diffusion rate across or a microporous or semipermeablemembrane. The inner core may substantially dissolve over time; however,in devices currently in use, the outer matrix does not dissolve.

Other implantable therapeutic systems involve matrix diffusion-typecontrolled drug delivery. The drug reservoir is formed by thehomogeneous dispersion of drug particles throughout a lipophilic orhydrophilic polymer matrix. The dispersion of drug particles in thepolymer matrix may be accomplished by blending the drug with a viscousliquid polymer or a semisolid polymer at room temperature, followed bycross-linking of the polymer, or by mixing the drug particles with amelted polymer at an elevated temperature. It can also be fabricated bydissolving the drug particles and/or the polymer in an organic solventfollowed by mixing and evaporation of the solvent in a mold at anelevated temperature or under vacuum. The rate of drug release from thistype of delivery device is not constant. Examples of this type ofimplantable therapeutic system are the contraceptive vaginal ring andCompudose implant. PCT/GB 90/00497 describes slow release glassy systemsfor formation of implantable devices. The described implants arebioabsorbable and need not be surgically removed. One skilled in the artcan adapt these drug delivery systems for delivering the drugscontemplated herein at the BONATH.

In microreservoir dissolution-controlled drug delivery, the drugreservoir, which is a suspension of drug particles in an aqueoussolution of a water-miscible polymer, forms a homogeneous dispersion ofa multitude of discrete, unleachable, microscopic drug reservoirs in apolymer matrix. The microdispersion may be generated by using ahigh-energy-dispersing technique. Release of the drug from this type ofdrug delivery device follows either an interfacial partition or a matrixdiffusion-controlled process. An example of this type of drug deliverydevice is the Syncro-Mate-C Implant.

Yet another formulation which may be adapted by one skilled in the artfor use in the present invention is described in U.S. Pat. No. 6,576,263(Truong, et al.), hereby incorporated by reference, which describes apreformed object for delivering an active agent for a subject, thepreformed object including crosslinked protein, and methods of makingand using.

Yet another formulation which may be adapted by one skilled in the artfor use in the present invention is described in U.S. Pat. No. 6,287,588(Shih, et al.), hereby incorporated by reference, which describes acomposition and method for releasing a bio-active agent or a drug withina biological environment in a controlled manner. The composition is adual phase polymeric agent-delivery composition comprising a continuousbiocompatible gel phase, a discontinuous particulate phase comprisingdefined microparticles and an agent to be delivered. A microparticlecontaining a bio-active agent is releasably entrained within abiocompatible polymeric gel matrix. The bio-active agent release may becontained in the microparticle phase alone or in both the microparticlesand the gel matrix. The release of the agent is prolonged over a periodof time, and the delivery may be modulated and/or controlled. Inaddition, a second agent may be loaded in some of the microparticlesand/or the gel matrix.

Yet another formulation which may be adapted by one skilled in the artfor use in the present invention is described in U.S. Pat. No. 7,364,568(Angel, et al.), hereby incorporated by reference, which describes atransdermal transport device includes a reservoir for holding aformulation of an active principle, and a needle with a bore extendingalong the length of the needle from a first end of the needle to asecond end of the needle. The second end is substantially aligned to aplane parallel to a body surface of a biological body when the device isplaced on the body surface. The device also includes an actuator whichpumps the formulation through the bore of the needle between a targetarea of the body and the reservoir.

In yet other embodiments of the invention, the dopamine agonist isinfused into the patient at the BONATH using technology known to beuseful for infusing other drugs, such as an insulin pump. One suchsystem, U.S. Pat. No. 7,354,420 (Steil, et al.), hereby incorporated byreference, describes a closed loop infusion system controls the ratethat fluid is infused into the body of a user. The closed loop infusionsystem includes a sensor system, a controller, and a delivery system.The sensor system includes a sensor for monitoring a condition of theuser. The sensor produces a sensor signal, which is representative ofthe condition of the user. The sensor signal is used to generate acontroller input. The controller uses the controller input to generatecommands to operate the delivery system. The delivery system infuses aliquid into the user at a rate dictated by the commands from thecontroller. Preferably, the sensor system monitors the glucoseconcentration in the body of the user, and the liquid infused by thedelivery system into the body of the user includes insulin.

The present invention is contemplated to encompass all implantable orinjectable formulations, e.g., the technologies described above, withthe inclusion of a drug(s) (e.g., dopamine agonist(s)), such that theadministration of a drug useful for treatment of disease state orcondition in humans via topical brainstem afferent stimulation(de-afferentation) therapy. Therefore, modifications of the inventionvia, e.g., the choice and/or amount of drug are considered to be obviousvariations of this disclosure and within the scope of the appendedclaims.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

The present invention will now be more fully described with reference tothe accompanying examples. It should be understood, however, that thefollowing description is illustrative only and should not be taken inany way as a restriction on the generality of the invention specifiedabove.

Example 1 Topical Formulation

An aqueous based apomorphine cream was produced using Lipoderm® as thecarrier. Lipoderm®/LIP is a commercially marketed compounding agent(from PCCA, Pharmaceutical Compounding Centers of America) having thefollowing ingredients: Ethoxydiglycol, Water (Aqua), Glycerin,C₁₂₋₁₅Alkyl Benzoate, Glyceryl Stearate, Dimethicone, Cetearyl Alcohol,Cetearyl Glucoside, Polyacrylamide, Cetyl Alcohol, Magnesium AluminumSilicate, Xanthan Gum, Aloe Vera (Aloe Barbadensis), Tocopheryl Acetate(Vitamin E Acetate), Prunus Amygadalus Amara (Bitter Almond) Kernel Oil,Vitis Vinifera (Grape) Seed Extract, Triticum Vulgare (Wheat) Germ Oil,Retinyl Palmitate (Vitamin A Palmitate), Ascorbyl Palmitate (Vitamin CPalmitate), Pro-Lipo Multi-emulsion Liposomic System, Tetrasodium EDTA,Phenoxyethanol, and Sodium Hydroxymethylglycinate. The concentration was1 mg of apomorphine in 1 ml of Lipoderm. The concentration ofapomorphine in the Lipoderm is 1 mg in 0.5 ml. Lipoderm is a whitishcream with no smell.

Example 2 Drug Study Using Formulation of Example 1

The efficacy of a topical apomorphine formulation was studied in sixhuman patients suffering from Parkinson's disease who presented to theauthor's neurologic clinic at a certain stage of “off state” in theirfunctioning. For each of these patients, an amount of the compoundedcream prepared in accordance with Example 1 containing approximately 1mg apomorphine (except 0.5 mg in one patient, E.K.) in 0.5 ml ofcompounding medium, was applied at the back of the neck at the hairline(BONATH) of the patient, so as to deliver the drug through topicalregional neuro-affective (TRNA) therapy.

The patients, who were all on other routine Parkinson's medications,were evaluated using the UPDRS Motor Scale pre and post-treatment withthe topical apomorphine. All patients had not had their respectiveParkinson's medications for 4-6 hours and thus were in their“off-states”. The UPDRS is an objectified observer-rated scale forevaluating Parkinson's disease that is used extensively in research. Thescale looks at 27 items with 0 to 4 ratings for each: 0 for normal and 4for the most extreme dysfunction. Accordingly, for a given patient, aUPDRS Motor Scale of 0 is normal and worse case scenario, 108 (27×4). Arepresentative UPDS form is presented as Table 1 below:

TABLE 1 UNIFIED PARKINSON'S DISEASE RATING SCALE (UPDRS) PART III: MotorExamination (The score to be completed incrementally, i.e. 0.0, 0.5,1.0, 1.5-4.0) 18. Speech: 0. Normal 1. Slight loss of expression,diction, and/or volume 2. Monotone, slurred but understandable;moderately impaired 3. Marked impairment, difficult to understand 4.Unintelligible 19. Facial Expression: 0. Normal 1. Minimal hypomimia,could be normal “poker face” 2. Slight but definitely abnormaldiminution of facial expression 3. Moderate hypomimia, lips parted someof the time 4. Masked or fixed facies with severe or complete loss offacial expression; lips parted ¼ inch or more 20. Tremor at rest: 20a)Face, lips, chin 0. Absent 20b) Right hand 1. Slight and infrequentlypresent 20c) Left hand 2. Mild in amplitude and persistent, or 20d)Right foot moderate in amplitude, bet only intermittently present 20e)Left foot 3. Moderate in amplitude and present most of the time 4.Marked in amplitude and present most of the time 21. Action or posturaltremor of hands:. 21a) Right 0. Absent 21b) Left 1. Slight; present withactions 2. Moderate in amplitude; present with action 3. Moderate inamplitude; present with posture-holding as well as with action 4. Markedin amplitude; interferes with feeding 22. Rigidity (judged on passivemovement of major joints with patient relaxed in sitting position;“cogwheeling” to be ignored: 22a) Neck 0. Absent 22b) Right upper 1.Slight or detectable only when activated by mirror or 22c) Left upperother movement 22d) Right lower 2. Mild to moderate 22e) Left lower 3.Marked but full range of motion easily achieved 4. Severe; range ofmotion achieved with difficulty 23. Finger taps (patient taps thumb withindex finger in rapid succession with widest amplitude possible, eachhand separately): 23a) Right 0. Normal 23b) Left 1. Mild slowing and/orreduction in amplitude 2. Moderately impaired; definite and earlyfatiguing, may have occasional arrests in movement 3. Severely impaired;frequent hesitation in initiating movements or arrests in ongoingmovement 4. Can barely perform the task 24. Hands movements (patientopens and closes hands in rapid succession with widest amplitudepossible, each hand separately): 24a) Right 0. Normal 24b) Left 1. Mildslowing and/or reduction in amplitude 2. Moderately impaired; definiteand early fatiguing; may have occasional arrests in movement 3. Severlyimpaired; frequent hesitation in initiating movements or arrests inongoing movement 4. Can barely perform the task 25. Rapid alternatingmovements of hand (pronation-supination movements of hands, verticallyor horizontally, with as large an amplitude as possible, both handssimultaneously): 25a) Right 0. Normal 25b) Left 1. Mild slowing and/orreduction in amplitude 2. Moderately impaired; definite and earlyfatiguing; may have occasional arrests in movement 3. Severely impaired;frequent hesitation in initiating movements or arrests in ongoingmovement 4. Can barely perform the task 26. Foot agility (patient tapsheel on ground in rapid succession, picking up entire leg; amplitudeshould be about 3 inches): 26a) Right 0. Normal 26b) Left 1. Mildslowing and/or reduction in amplitude 2. Moderately impaired; definiteand early fatiguing; may have occassional arrests in movement 3.Severely impaired; frequent hesitation in initiating movements orarrests in ongoing movement 4. Can barely perform the task 27. Arisingfrom chair(patient attempts to arise from a straight-backed wood ormetal chair, with arms folded across chest): 27a) Right 0. Normal 27b)Left 1. Slow or may need more than one attempt 2. Pushes self up fromarms or seat 3. Tends to fall back and may have to try more than on timebut can get up without help 4. Unable to arise without help PART III:Motor Examination (The score to be completed incrementally, i.e. 0.0,0.5, 1.0, 1.5-4.0) 28. Posture: 0. Normal effect 1. Not quite erect,slightly stooped posture; couid be normal for older person 2. Moderatelystooped posture, definitely abnormal; can be slightly leaning to oneside 3. Severely stooped posture with kyphosis: can be moderatelyleaning to one side 4. Marked flexion, with extreme abnormality ofposture 29. Gait: 0. Normal 1. Walks slowly; may shuffle with shortsteps, but no festination or propulsion 2. Walks with difficulty butrequires little or so assistance, may have some festination, shortsteps, or propulsion 3. Severe disturbance of gait; requires assistance4. Cannot walk at all, even with assistance 30. Postural stability(response to sudden posterior displacement produced by pull on shoulderswhile patient erect, with eyes open and feet slightly apart; patient isprepared): 0. Normal 1. Retropulsion, but recovers unaided 2. Absence ofpostural response; would fall if not caught by examiner 3. Veryunstable; tends to lose balance spontaneously 4. Unable to stand withoutassistance 31. Body bradykinesia and hypokinesia (combining slowness,hesitancy, decreased arm swing, small amplitude and poverty of movementin general): 0. None 1. Minimal slowness, giving movement a deliberatecharacter; could be normal for some persons; possible reduced amplitude2. Mild degree of slowness and poverty of movement that is definitelyabnormal; alternately, some reduced amplitude 3. Moderate slowness;poverty or small amplitude of movement 4. Marked slowness; poverty orsmall amplitude of movement

The results of the study of Example 2 am set forth in Table 2 below:

TABLE 2 CLINICAL RESPONSE OF PARKINSON'S PATIENTS IN THE “OFF-STATE” TOTOPICAL APOMORPHINE THERAPY: CHANGE IN UPDRS MOTOR SCORES* Current UPDRSDuration Parkinsons Motor Patient Sex Age Parkinsons Medications PrePost Diff EB F 86 8 years Stalevo 51 32 19 (Sinemet & Comtan) GV M 87 12Stalevo 38 18 20 EK F 75 6 Sinemet and 36 19 17 Mirapex WH M 88 11Sinemet and 51 31 20 Mirapex SK F 89 5 Sinemet 66 52 14 IR M 64 10Sinemet, 57 34 23 Mirapex and Amantatine *1.0 mg of apomorphine in 0.5ml Lipoderm except 0.5 mg in patient (E.K.) Patients were re-examinedwithin ½ hour after topical application.

As can be appreciated from Table 2, these 6 patients were fairlysignificantly affected by their disease. Within 15-30 minutes afterapplication of the compounded apomorphine cream, they were all improvedsignificantly. The average UPDRS score post-treatment was 31, indicatingan average improvement of 19 points. The duration of improved functionalstate was observed to be from 2%₂ to 26 hours, representing the timeperiod patients felt they were able to function off their usualParkinson's medications due to the positive therapeutic effect of thetopical apomorphine. After this period, all patients returned to theirprevious drug regimen, which consisted of taking Parkinson's medications3-4 times per day. By their own accounts and those of their care-takers,their current therapy was considered sub-optimal. This was evident onformal clinical exam and documented by the UPDRS, as noted in Table 2.The only significant side-effects expressed were transient fatigue anddizziness, in patients E.K. and S.K.

Video-tape of pre and post-treatment states with topical apomorphine wasperformed on several patients, additionally documenting clinicalimprovement.

Example 3 Additional Clinical Experience—Parkinson's Disease

In the inventor's out-patient neurology practice, in excess of 60 PDpatients have been treated with topical apomorphine employing theprinciples of topical regional neuroaffective (TRNA) therapy in similarfashion as in Example 2. That experience suggests topical apomorphinealleviates clinical symptoms of PD in a measurable way over 85% of thetime when patients are treated in the “off-state” and exhibiting suchsymptoms: tremor, rigidity, postural instability, and reducedspontaneity, among others. Symptom improvement was clinically evident toboth the patient and the treating physician within 15 minutes of topicaldrug application. No appreciable side-effects were noted. Clinicalbenefit lasted, on the average, 4 hours, with some patients reportingover 10 hours. Formal double-blind, placebo-controlled, cross-overlong-term studies are contemplated.

Example 4 TRNA Therapy in Tremor

In the inventor's out-patient neurology practice, approximately 20patients with tremor have been treated with topical apomorphine insimilar fashion as in Example 2. Improvement in tremor not attributed toParkinson's disease has also been noted with TRNA apomorphine therapy.This has consisted of patients with benign essential/familial tremor aswell as tremor associated with Multiple Sclerosis, stroke disease, anddegenerative CNS conditions such as cerebellar degeneration.

The inventor treated 5 patients with benign essential tremor. They wereeither all on their tremor medications at the time or had given up ondrug therapy because of side-effects. One 74 yr. old lady (on video),with tremor since age 19, was on 4 meds when the inventor treated her on3 occasions. She responded dramatically (tremor improved over 70%) eachtime and is now using the topical apomorphine (1 mg/0.5 ml) 2×/day on aregular basis. All the other patients also responded to 1 mg ofapomorphine to varying degrees—anywhere from 30-80% reduction in tremor.

The inventor also treated 3 patients with MS related tremor. They alsoall responded with 50-80% reduction.

The inventor also treated 2 patients with stroke related tremor. One hadbeen severely affected by tremor and incoordination for over 10 yearsand she responded dramatically. As of filing, this patient is using iton a regular basis: 1 mg once to twice a day. The other patient alsoimproved but the cost of drug from the compounding pharmacy wasprohibitive.

The inventor has treated 2 patients with CNS degeneration related tremor(cerebellar degeneration); one is 46 yr. old female, the other a 20 yr.old male (video taped). As of filing, both responded and are using thecream 2×/day. Both these patients had either failed other drugs or couldnot tolerate them.

The balance of the tremor patients, 6 patients, were of uncertainetiology. Some of them had components suggestive of early Parkinson'sDisease (PD) or tremor predominant PD. In these, the response waspresent but not as dramatic, 30-50% reduction.

The duration of improvement of tremor in all these patients was onaverage 4 hours.

Example 5 Dystonia and Torticollis

In the inventor's out-patient neurology practice, several patients withcervical dystonia and torticollis have been observed to improve withtopical apomorphine administered in similar fashion as in Example 2.Some of these patients also exhibited improvement in the spasticity thatinvolved aspects of their bodies when present. In patients withsignificant rigidity and dystonia, the reduction in muscle tone wasnoticeably accompanied by an overall improved affect and spontaneity.This may be attributed to diminished pain and disability associated withthe dystonia but other mechanisms associated with TRNA apomorphinetherapy need also to be considered. This phenomenon was also observed inParkinson's Disease (PD) patients with significant rigidity and motorcomplications improved cognitive abilities and speech was also observedin some of these patients. These observations require further detailedstudy.

The inventor has treated 3 patients with cervical dystonia andtorticollis. One patient was treated three times and she continues touse 1 mg apomorphine twice a day on her own for relief of symptoms. Avideo exists on this patient. The other two patients also responded tovarying degrees that was noted by family members.

When PD was associated with significant rigidity, speech difficulty, anddistress (both physically and emotionally), the response appeared to bethe most dramatic. All patients reported a “calming and relaxing” effectwhich was obvious in their facial expressions. Speech was alsosignificantly improved. In the 15 patients the inventor treated in anuncompleted trial (discontinued for reasons other than the treatment),speech, swallow (by video), and cognition were documented as improved.In these 15 patients, active and placebo were given in 5 patients twiceand once each for the remaining 10 patients.

Example 6 Other Applications of TRNA Therapy in Clinical Practice

The inventor has also used topical clonidine and rivastigmine in theform of currently commercially available transdermal patches (CatapressTTS and Exelon patch, respectively) applied to the posterior cervicalregion (back of the neck at the hairline, “BONATH”) to capitalize on theprinciples of TRNA delivery. These transdermal patches were used inpatients clinically unresponsive to the usual methods of treatment withthese patches—placement at the usual sites of placement on the body. Inplacing the transdermal patches at the BONATH, more efficient andeffective therapeutic action of these 2 drugs is elicited.

The inventor administered Catapres TTS® 0.1 mg patch at the BONATH on afemale patient-52 yr. old who had suffered an intracranial hemorrhagefrom a ruptured aneurysm. She had uncontrolled central hypertensiondespite 4 meds and had also failed traditional placement therapy withCatapres. The patch was placed at the BONATH and after 10-15 minutes,the patient's BP dropped from 240/180 to 180/110, still unacceptable butbetter than what it had been for years. The patient discontinuedapplication of the patch at the BONATH after a period of time due toapparent headaches and remains with severe hypertension which has beendeemed incurable by cardiologists and renal physicians.

With respect to the Exelon® patch, the inventor is administering thispatch at a dose of 4.6 mg/24 hr patch daily at the BONATH in 6 patientsat the time of filing. The patients are tolerating this treatment, butit is still too early to determine the effect on their dementia.

One of the problems with systemic cholinesterase therapy (whether thetreatment is with Aricept®, Exelon®, or Reminyl®), is that of GIside-effects (especially nausea and upset stomach). TRNA therapy appearsnot to have this. But, still the patch was designed for absorption intothe bloodstream and may get into the systemic circulation whenadministered at the BONATH. It is hypothesized that, when madespecifically for BONATH application, the dose (particularly tissuepenetration) from a patch could be much lower and for a more prolongeddelivery, e.g., from about 3 days to about 1 week.

Conclusions Regarding Examples 2-6

These preliminary open-label findings in an outpatient office settingsuggest potential utility for apomorphine TRNA therapy in the managementof Parkinson's Disease (PD) and other conditions. This form ofapomorphine has also been used in benign essential tremor and tremorassociated with multiple sclerosis (MS), stroke, and CNS degenerativeprocesses, such as cerebellar degeneration, with similar results. Noformal blinded, placebo-controlled studies have been performed at thistime; however, preliminary trials using placebo (compounding mediumalone) and active drug suggest the validity of the reported findings. Adouble-blind, placebo-controlled, crossover study is deemed necessary toestablish “proof of concept” and confirm these preliminary results.

The examples provided above are not meant to be exclusive. Many othervariations of the present invention would be obvious to those skilled inthe art, and are contemplated to be within the scope of the appendedclaims.

The hypotheses of the inventor provided throughout the specification arefor possible explanation purposes only, and are not meant to be limitingin any way.

1: A method of treating pain in a human patient, comprisingadministering a drug for the treatment of neuropathic and/or neurogenicpain which is an opioid analgesic in a therapeutically effective amountto treat the disease state or condition, to the back of the neck at thehairline in close proximity to and under or on the area of skin abovethe brain stem to provide regional neuro-affective therapy to the humanpatient. 2: The method of claim 1, wherein the drug is selected from thegroup consisting of morphine, codeine, dihydrocodeine, hydrocodone,hydromorphone, nicomorphine, oxycodone, oxymorphone, fentanyl,alphamethylfentanyl, alfentanil, sufentanil, remifentanil, carfentanyl,ohmefentanyl, thebaine, oripavine, diacetylmorphine (heroin),phenylpiperidines such as pethidine (meperidine) and ketobemidone,allylprodine, prodine, propoxyphene, dextropropoxyphene, dextromoramide,bezitramide, piritramide, methadone, dipipanone, levomethadyl Acetate(LAAM), loperamide, diphenoxylate, dezocine, pentazocine, phenazocine,buprenorphine, dihydroetorphine, etorphine, butorphanol, nalbuphine,levorphanol, levomethorphan, lefetamine, meptazinol, tilidine, tramadol,tapentadol, and mixtures thereof.
 3. (canceled) 4: The method of claim2, wherein the drug is selected from the group consisting of morphine,codeine, dihydrocodeine, hydrocodone, hydromorphone, oxycodone,oxymorphone, fentanyl, sufentanil, tramadol, and mixtures thereof. 5:The method of claim 2, wherein the drug comprises morphine. 6-11.(canceled) 12: The method of claim 1, wherein the drug is used in thetreatment of neuropathic and/or neurogenic pain. 13-24. (canceled) 25:The method of claim 1, wherein the drug is formulated in apharmaceutically acceptable immediate release topical carrier. 26: Themethod of claim 25, wherein the carrier is aqueous-based. 27: The methodof claim 1, further comprising formulating the drug in apharmaceutically acceptable immediate release aqueous-based carrier, andapplying a sufficient amount to the back of the neck at the hairline(“BONATH”) of the human patient such that the onset of clinical effectoccurs in less than about 30 minutes.
 28. (canceled) 29: The method ofclaim 27, 25, wherein the carrier is a gel or cream. 30: The method ofclaim 29, further comprising adding at least one adjuvant selected fromthe group consisting of a penetration enhancer, antioxidant, stabilizer,and mixtures thereof to the carrier. 31: The method of claim 1, whereinthe drug is incorporated into a sustained release transdermal deliverysystem which is capable of delivering the drug through the skin of ahuman patient over a 24 hour period, the transdermal delivery systembeing capable of delivering the drug in such amounts for a time periodfrom about 1 to about 7 days. 32: The method of claim 31, wherein thetransdermal delivery system is selected from the group consisting of atransdermal patch, a transdermal plaster, a transdermal disc, and aniontophoretic transdermal device. 33-34. (canceled) 35: The method ofclaim 1, wherein the drug is administered via injection in an immediaterelease pharmaceutically acceptable carrier for injection. 36: Themethod of claim 1, wherein the drug is administered via injection orimplantation in a controlled release carrier to provide a prolongedeffect of the drug. 37: The method of claim 1, wherein the drug isincorporated into a delivery system selected from the group consistingof a gel, a matrix, microparticles, a pellet, an insert, a colloidalmaterial, and mixtures of any of the foregoing. 38-51. (canceled) 52: Amethod for treating neuropathic and/or neurogenic pain in a humanpatient, comprising topically administering an opioid analgesic in animmediate release topical formulation at the back of the neck to providetreatment of neuropathic and/or neurogenic pain in the human patient inless than about 30 minutes after said topical administration. 53: Themethod of claim 52, wherein the drug is selected from the groupconsisting of morphine, codeine, dihydrocodeine, hydrocodone,hydromorphone, oxycodone, oxymorphone, fentanyl, sufentanil, tramadol,and mixtures thereof. 54: The method of claim 52, wherein the drugcomprises morphine. 55: The method of claim 52, wherein the drugcomprises tramadol. 56: The method of claim 52, wherein the topicalformulation is applied in the form of a cream or gel.